Compounds for inflammation and immune-related uses

ABSTRACT

The invention relates to compounds of structural formula (I) and structural formula (VI): 
                         
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R, R 1 , R 2 , Z, L, and n are defined herein. Those compounds are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

RELATED APPLICATIONS

This application is a continuation of U.S. nonprovisional applicationSer. No. 13/948,541, filed Jul. 23, 2013, which is a divisional of U.S.nonprovisional application Ser. No. 11/340,184, filed Jan. 25, 2006, nowU.S. Pat. No. 8,518,950, which claims the benefit of U.S. provisionalapplication No. 60/646,683, filed on Jan. 25, 2005, the entire teachingsof which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to biologically active chemical compounds, namelypyrazinyl, pyrimidinyl and pyridazinyl derivatives that may be used forimmunosuppression or to treat or prevent inflammatory conditions,allergic, disorders and immune disorders.

BACKGROUND OF THE INVENTION

Inflammation is a mechanism that protects mammals from invadingpathogens. However, while transient inflammation is necessary to protecta mammal from infection, uncontrolled inflammation causes tissue damageand is the underlying cause of many illnesses. Inflammation is typicallyinitiated by binding of an antigen to T-cell antigen receptor. Antigenbinding by a T-cell initiates calcium influx into the cell via calciumion channels, such as Ca²⁺-release-activated Ca²⁺ channels (CRAC).Calcium ion influx in turn initiates a signaling cascade that leads toactivation of these cells and an inflammatory response characterized bycytokine production.

Interleukin 2 (IL-2) is a cytokine that is secreted by T cells inresponse to calcium ion influx into the cell. IL-2 modulatesimmunological effects on many cells of the immune system. For example,it is a potent T cell mitogen that is required for T cell proliferation,promoting their progression from G1 to S phase of the cell cycle; itstimulates the growth of NK cells; and it acts as a growth factor to Bcells and stimulates antibody synthesis.

IL-2, although useful in the immune response, can cause a variety ofproblems. IL-2 damages the blood-brain barrier and the endothelium ofbrain vessels. These effects may be the underlying causes ofneuropsychiatric side effects observed under IL-2 therapy, e.g. fatigue,disorientation and depression. It also alters the electrophysiologicalbehaviour of neurons.

Due to its effects on both T and B cells, IL-2 is a major centralregulator of immune responses. It plays a role in inflammatoryreactions, tumour surveillance, and hematopoiesis. It also affects theproduction of other cytokines, inducing IL-1, TNF-α and TNF-β secretion,as well as stimulating the synthesis of IFN-γ in peripheral leukocytes.

T cells that are unable to produce IL-2 become inactive (anergic). Thisrenders them potentially inert to any antigenic stimulation they mightreceive in the future. As a result, agents which inhibit IL-2 productioncan be used for immunosuppression or to treat or prevent inflammationand immune disorders. This approach has been clinically validated withimmunosuppressive drugs such as cyclosporin, FK506, and RS61443. Despitethis proof of concept, agents that inhibit IL-2 production remain farfrom ideal. Among other problems, efficacy limitations and unwanted sideeffects (including dose-dependant nephrotoxicity and hypertension)hinder their use.

Over production of proinflammatory cytokines other than IL-2 has alsobeen implicated in many autoimmune diseases. For example, Interleukin 5(IL-5), a cytokine that increases the production of eosinophils, isincreased in asthma. Overproduction of IL-5 is associated withaccumulation of eosinophils in the asthmatic bronchial mucosa, a hallmark of allergic inflammation. Thus, patients with asthma and otherinflammatory disorders involving the accumulation of eosinophils wouldbenefit from the development of new drugs that inhibit the production ofIL-5.

Interleukin 4 (IL-4) and interleukin 13 (IL-13) have been identified asmediators of the hypercontractility of smooth muscle found ininflammatory bowel disease and asthma. Thus, patients with asthma andinflammatory bowel disease would benefit from the development of newdrugs that inhibit IL-4 and IL-13 production.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a regulatorof maturation of granulocyte and macrophage lineage population and hasbeen implicated as a key factor in inflammatory and autoimmune diseases.Anti-GM-CSF antibody blockade has been shown to ameliorate autoimmunedisease. Thus, development of new drugs that inhibit the production ofGM-CSF would be beneficial to patients with an inflammatory orautoimmune disease.

There is a continuing need for new drugs which overcome one or more ofthe shortcomings of drugs currently used for immunosuppression or in thetreatment or prevention of inflammatory disorders, allergic disordersand autoimmune disorders. Desirable properties of new drugs includeefficacy against diseases or disorders that are currently unbeatable orpoorly treatable, new mechanism of action, oral bioavailability and/orreduced side effects.

This invention meets the above-mentioned needs by providing certainpyrazinyl and pyridazinyl derivatives that inhibit the activity of CRACion channels and inhibit the production of IL-2, IL-4, IL-5, IL-13,GM-CSF, TNF-α, and IFNγ. These compounds are particularly useful forimmunosuppression and/or to treat or prevent inflammatory conditions,allergic disorders and immune disorders.

In one embodiment, the invention relates to compounds of formula (I):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   L is a linker selected from the group consisting of —NRCH₂—,        —CH₂NR—, —C(O)—, —NR—C(O), —C(O)—NR—, —C(S)—, —NR—C(S)—,        —C(S)—NR—;    -   each Z is independently selected from the group consisting of a        lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower        alkyl sufanyl, cyano, nitro, or lower haloalkoxy;    -   R, for each occurrence is independently selected from —H, an        alkyl, —C(O)R₅, or —C(O)OR₅;    -   R₁ is an optionally substituted aryl or an optionally        substituted heteroaryl;    -   R₂ is an optionally substituted cycloalkyl, an optionally        substituted cycloalkenyl, an optionally substituted aryl or an        optionally substituted heteroaryl;    -   R₅, for each occurrence, is independently, H, an alkyl, a        cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl,        or a heteraralkyl; and    -   n is 0, 1 or 2.

In another embodiment, the invention relates to compounds of formula(V):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   R₁₂ is an aryl or a heteroaryl, wherein the aryl and heteroaryl        are optionally substituted with one or more substituent selected        from the group consisting of an optionally substituted alkyl, an        optionally substituted alkenyl an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl an optionally        substituted heteroaryl, an optionally substituted aralkyl, or an        optionally substituted heteraralkyl, a halo, cyano, nitro,        —OR₁₇, —SR₁₇, —S(O)_(p)R₁₇, —S(O)_(p)OR₁₇, —OS(O)_(p)R₁₇,        —OS(O)_(p)OR₁₇, —NR₁₇S(O)_(p)R₁₇, —S(O)_(p)NR₁₅R₁₆, —NR₁₅R₁₆,        —C(X₃)R₁₇, —C(X₃)OR₁₇, —C(X₃)SR₁₇, —C(X₃)NR₁₅R₁₆, —NR₁₇C(X₃)R₁₈,        —NR₁₇C(X₃)OR₁₈, —NR₁₇C(X₃)SR₁₈, —NR₁₇C(X₃)NR₁₅R₁₆, —OC(X₃)R₁₇,        —OC(X₃)OR₁₇, —OC(X₃)SR₁₇, —SC(X₃)OR₁₇, —SC(X₃)SR₁₇,        —OC(X₃)NR₁₅R₁₆, —SC(X₃)NR₁₅R₁₆, —P(X₄)(X₅R₁₇)₂,        —X₅P(X₄)(X₅R₁₇)₂, —P(X₄)(R₁₇)₂, —P(X₄)(R₁₇)(X₅R₁₇);    -   R₁₃ is a cycloalkyl, a cycloalkenyl, an aryl, or a heteroaryl,        wherein the cycloalkyl, cycloalkenyl, aryl, or heteroaryl are        optionally substituted with one or more substituents selected        from the group consisting of an optionally substituted alkyl, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted cycloalkenyl, an optionally substituted aryl, an        optionally substituted heteroaryl, an optionally substituted        aralkyl, or an optionally substituted heteraralkyl, a halo,        cyano, nitro, a haloalkyl, —OR₁₇, —SR₁₇, —S(O)_(p)R₁₇,        —S(O)_(p)OR₁₇, —OS(O)_(p)R₁₇, —OS(O)_(p)OR₁₇, —S(O)_(p)NR₁₅R₁₆,        —NR₁₅R₁₆, —C(X₃)R₁₇, —C(X₃)OR₁₇, —C(X₃)SR₁₇, —C(X₃)NR₁₅R₁₆,        —NR₁₇C(X₃)R₁₈, —NR₁₇C(X₃)OR₁₈, —NR₁₇C(X₃)SR₁₈,        —NR₁₇C(X₃)NR₁₅R₁₆, —OC(X₃)R₁₇, —OC(X₃)OR₁₇, —OC(X₃)SR₁₇,        —SC(X₃)OR₁₇, —SC(X₃)SR₁₇, —OC(X₃)NR₁₅R₁₆; —SC(X₃)NR₁₅R₁₆,        —P(X₄)(X₅R₁₇)₂, —X₅P(X₄)(X₅R₁₇)₂; —P(X₃)(R₁₇)₂,        —P(X₄)(R₁₇)(X₅R₁₇);    -   R₁₄, for each occurrence is independently selected from —H, an        alkyl, —C(O)R₂₀, or —C(O)OR₂₀;    -   R₁₅ and R₁₆, for each occurrence are, independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₁₅ and R₁₆ taken together with the nitrogen to which they        are attached are an optionally substituted heterocyclyl or        optionally substituted heteroaryl;    -   R₁₇ and R₁₈, for each occurrence are, independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₁₉, for each occurrence, is independently —H, a halo, an alkyl,        —OR₁₇, —NR₁₅R₁₆, —C(O)R₁₇, —C(O)OR₁₇, or —C(O)NR₁₅R₁₆;    -   R₂₀, for each occurrence, is independently, H or an alkyl;    -   X₃ is ═O, ═S, or ═N—R₁₉;    -   X₄ is ═O or ═S;    -   X₅ is —O— or —S—;    -   p is 1 or 2; and    -   Z and n are defined as for formula (I).

In another embodiment, the invention relates to compounds of formula(VI):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   R, R₁, R₂, Z and n are defined as for formula (I).

In another embodiment, the invention relates to compounds of formula(IX):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   R₂₁ is an alkyl which is optionally substituted with one or more        substituents selected from the group consisting of an optionally        substituted alkynyl, an optionally substituted cycloalkyl, an        optionally substituted cycloalkenyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl, a        halo, cyano, nitro, a haloalkyl, —OR₁₇, —SR₁₇, —S(O)_(p)R₁₇,        —S(O)_(p)OR₁₇, —OS(O)_(p)R₁₇, —OS(O)_(p)OR₁₇, —S(O)_(p)NR₁₅R₁₆,        —NR₁₅R₁₆, —C(X₃)OR₁₇, —C(X₃)OR₁₇, —C(X₃)SR₁₇, —C(X₃)NR₁₅R₁₆,        —NR₁₇C(X₃)R₁₈, —NR₁₇C(X₃)OR₁₈, —NR₁₇C(X₃)SR₁₈,        —NR₁₇C(X₃)NR₁₅R₁₆, —OC(X₃)R₁₇, —OC(X₃OR₁₇, —OC(X₃)SR₁₇,        —SC(X₃)OR₁₇, —SC(X₃)R₁₇, —OC(X₃)NR₁₅R₁₆, —SC(X₃)NR₁₅R₁₆,        —P(X₄)(X₅R₁₇)₂, —X₅P(X₄R₁₇)₂, —P(X₄)(R₁₇)₂, —P(X₄)(X₅R₁₇);    -   R₁, Z and n are defined as for formula (I); and    -   R₁₅, R₁₆, R₁₇, R₁₈, X₃, X₄, X₅, and p are defined as for formula        (V).

In another embodiment, the invention relates to compounds of formula(XII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₈ and X₉ are N and X₁₀ and X₁₁ are CH or CZ; or X₁₀ and X₁₁ are        N and X₈ and X₉ are CH or CZ;    -   L, Z, R₁, and R₂ are defined as for formula (I).

A compound of the invention or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof is particularly useful inhibitingimmune cell (e.g., T-cells and/or B-cells) activation (e.g., activationin response to an antigen). In particular, a compound of the inventionor a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof can inhibit the production of certain cytokines that regulateimmune cell activation. For example, a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereofcan inhibit the production of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α,INF-γ or combinations thereof. Moreover, a compound of the invention ora pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof can modulate the activity of one or more ion channel involved inactivation of immune cells, such as CRAC ion channels.

In one embodiment, compounds of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof are particularlyuseful for inhibiting mast cell degranulation. Mast cell degranulationhas been implicated in allergic reactions.

A compound of the invention or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof is particularly useful forimmunosuppression or for treating or preventing inflammatory conditions,allergic disorders, and immune disorders.

The invention also encompasses pharmaceutical compositions comprising acompound of the invention or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof; and a pharmaceuticallyacceptable carrier or vehicle. These compositions may further compriseadditional agents. These compositions are useful for immunosuppressionand treating or preventing inflammatory conditions, allergic disordersand immune disorders.

The invention further encompasses methods for treating or preventinginflammatory conditions, allergic disorders, and immune disorders,comprising administering to a subject in need thereof an effectiveamount of a compound of the invention or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, or a pharmaceuticalcomposition comprising a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof. These methodsmay also comprise administering to the subject an additional agentseparately or in a combination composition with the compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof.

The invention further encompasses methods for suppressing the immunesystem of a subject, comprising administering to a subject in needthereof an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, or a pharmaceutical composition comprising a compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof. These methods may also comprise administering to thesubject an additional agent separately or in a combination compositionwith the compound of the invention or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof.

The invention further encompasses methods for inhibiting immune cellactivation, including inhibiting proliferation of T cells and/or Bcells, in vivo or in vitro comprising administering to the cell aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt solvate, clathrate, or prodrug thereof or apharmaceutical composition comprising a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

The invention further encompasses methods for inhibiting cytokineproduction in a cell (e.g., IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α,and/or INF-γ production) in vivo or in vitro comprising administering toa cell an effective amount of a compound of the invention or apharmaceutically acceptable, salt, solvate, clathrate, or prodrugthereof or a pharmaceutical composition comprising a compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof.

The invention further encompasses methods for modulating ion channelactivity (e.g., CRAC) in vivo or in vitro comprising administering aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof or apharmaceutical composition comprising a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

All of the methods of this invention may be practice with a compound ofthe invention alone, or in combination with other agents, such as otherimmunosuppressive agents, anti-inflammatory agents, agents for thetreatment of allergic disorders or agents for the treatment of immunedisorders.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise specified, the below terms used herein are defined asfollows:

As used herein, the term an “aromatic ring” or “aryl” means a monocyclicor polycyclic-aromatic ring or ring radical comprising carbon andhydrogen atoms. Examples of suitable aryl groups include, but are notlimited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, andnaphthyl, as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted orsubstituted with one or more substituents (including without limitationalkyl (preferably, lower alkyl or alkyl substituted with one or morehalo), hydroxy, alkoxy (preferably, lower alkoxy), alkylsylfanyl, cyano,halo, amino, and nitro. In certain embodiments, the aryl group is amonocyclic ring, wherein the ring comprises 6 carbon atoms.

As used herein, the term “alkyl” means a saturated straight chain orbranched non-cyclic hydrocarbon typically having from 1 to 10 carbonatoms. Representative saturated straight chain alkyls include methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyland n-decyl; while saturated branched alkyls include isopropyl,sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl,3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl,2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl,3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl,2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Alkylgroups included in compounds of this invention may be optionallysubstituted with one or more substituents. Examples of substituentsinclude, but are not limited to, amino, alkylamino, alkoxy,alkylsulfanyl, oxo, halo, acyl, nitro, hydroxyl, cyano, aryl, alkylaryl,aryloxy, arylsulfanyl, arylamino, carbocyclyl, carbocyclyloxy,carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy,heterocyclylamino, heterocyclylthio, and the like. In addition, anycarbon in the alkyl segment may be substituted with oxygen (═O), sulfur(═S), or nitrogen (═NR²², wherein R²² is —H, an alkyl, acetyl, oraralkyl). Lower alkyls are typically preferred for the compounds of thisinvention.

The term alkylene refers to an alkyl group or a cycloalkyl group thathas two points of attachment to two moieties (e.g., {—CH₂—}, —{CH₂CH₂—},

etc., wherein the brackets indicate the points of attachment). Alkylenegroups may be substituted or unsubstituted with one or moresubstituents.

An aralkyl group refers to an aryl group that is attached to anothermoiety via an alkylene linker. Aralkyl groups can be substituted orunsubstituted with one or more substituents.

The term “alkoxy,” as used herein, refers to an alkyl group which islinked to another moiety through an oxygen atom. Alkoxy groups can besubstituted or unsubstituted with one or more substituents.

The term “alkylsulfanyl” as used herein, refers to an alkyl group whichis linked to another moiety through a divalent sulfur atom.Alkylsulfanyl groups can be substituted or unsubstituted with one ormore substituents.

The term “arylsulfanyl,” as used herein, refers to an aryl group whichis linked to another moiety through a divalent sulfur atom. Arylsulfanylgroups can be substituted or unsubstituted with one or moresubstituents.

The term “alkyl ester” as used herein, refers to a group represented bythe formula —C(O)OR₃₂, wherein R₃₂ is an alkyl group. A lower alkylester is a group represented by the formula —C(O)OR₃₂, wherein R₃₂ is alower alkyl group.

The term “heteroalkyl,” as used herein, refers to an alkyl group whichhas one or more carbons in the alkyl chain replaced with an —O—, —S— or—NR₂₇—, wherein R₂₇ is H or a lower alkyl. Heteroalkyl groups can besubstituted or unsubstituted with one or more substituents.

The term “alkylamino,” as used herein, refers to an amino group in whichone hydrogen atom attached to the nitrogen has been replaced by an alkylgroup. The term “dialkylamino,” as used herein, refers to an amino groupin which two hydrogen atoms attached to the nitrogen have been replacedby alkyl groups, in which the alkyl groups can be the same or different.Alkylamino groups and dialkylamino groups can be substituted orunsubstituted with one or more substituents.

As used herein, the term “alkenyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at least one carbon-carbon double bond. Representative straightchain and branched alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl,isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,1-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl,3-decenyl and the like. Alkenyl groups can be substituted orunsubstituted with one or more substituents.

As used herein, the term “alkynyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at least one carbon-carbon triple bond. Representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,4-pentynyl-1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl,8-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl,8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl and the like. Alkynyl groupscan be substituted or unsubstituted with one or more substituents.

As used herein, the term “cycloalkyl” means a saturated, mono- orpolycyclic alkyl radical typically having from 3 to 14 carbon atoms.Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly,decahydronaphthyl, octahydropentalene, bicycle[1.1.1]pentanyl, and thelike. Cycloalkyl groups can be substituted or unsubstituted with one ormore substituents.

As used herein, the term “cycloalkenyl” means a cyclic non-aromaticalkenyl radical having at least one carbon-carbon double bond in thecyclic system and typically having from 5 to 14 carbon atoms.Representative cycloalkenyls include cyclopentenyl, cyclopentdienyl,cyclohexenyl cyctohexadienyl cyctoheptenyl, cycloheptadienyl,cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl,cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl,cyclodecadienyl and the like. Cycloalkenyl groups can be substituted orunsubstituted with one or more substituents.

As used herein, the term “heterocycle” or “heterocyclyl” means amonocyclic or polycyclic heterocyclic ring (typically having 3- to14-members) which is either a saturated ring or an unsaturatednon-aromatic ring. A 3-membered heterocycle can contain up to 3heteroatoms, and a 4- to 14-membered heterocycle can contain from 1 toabout 8 heteroatoms. Each heteroatom is independently selected fromnitrogen, which can be quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. The heterocycle may be attached via anyheteroatom or carbon atom. Representative heterocycles includemorpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, 4H-pyranyl, tetrahydropyindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like. A heteroatom may be substituted with a protecting group knownto those of ordinary skill in the art, for example, the hydrogen on anitrogen may be substituted with a tert-butoxycarbonyl group.Furthermore, the heterocyclyl may be optionally substituted with one ormore substituents (including without limitation a halo, an alkyl, ahaloalkyl, or aryl). Only stable isomers of such substitutedheterocyclic groups are contemplated in this definition.

As used herein, the term “heteroaromatic” or “heteroaryl” means amonocyclic or polycyclic heteroaromatic ring (or radical thereof)comprising carbon atom ring members and one or more heteroatom ringmembers (such as, for example, oxygen, sulfur or nitrogen). Typically,the heteroaromatic ring has from 5 to about 14 ring members in which atleast 1 ring member is a heteroatom selected from oxygen, sulfur andnitrogen. In another embodiment, the heteroaromatic ring is a 5 or 6membered ring and may contain from 1 to about 4 heteroatoms. In anotherembodiment the heteroaromatic ring system has a 7 to 14 ring members andmay contain from 1 to about 7 heteroatoms. Representative heteroarylsinclude pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl,indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothizolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl, thiadiazolyl,pyrazinyl, quinolyl, isoquniolyl, indazolyl, benzoxazolyl, benzofuryl,benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl, tetrazolyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzoxadiazolyl, iodolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl,qunizaolinyl, purinyl, pyrrolo[2,3]pyrimidyl, pyrazalo[3,4]pyrimidyl orbenzo(b)thienyl and the like. Heteroaryl groups may be optionallysubstituted with one or more substituents

A heteroaralkyl group refers to a heteroaryl group that is attached toanother moiety via an alkylene linker. Heteroaralkyl groups can besubstituted or unsubstituted with one or more substituents.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

As used herein, the term “haloalkyl” means an alkyl group in which oneor more —H is replaced with a halo group. Examples of haloalkyl groupsinclude —CF₃, —CHF₂, —CCl₃, —CH₂CH₂Br, —CH₂CH(CH₂CH₂Br)CH₃, —CHICH₃, andthe like.

As used herein, the term “haloalkoxy” means an alkoxy group in which oneor more —H is replaced with a halo group. Examples of haloalkoxy groupsinclude —OCF₃ and —OCHF₂.

The terms “bioisostere” and “bioisosteric replacement” have the samemeanings as those generally recognized in the art. Bioisosteres areatoms, ions, or molecules in which the peripheral layers of electronscan be considered substantially identical. The term bioisostere isusually used to mean a portion of an overall molecule, as opposed to theentire molecule itself. Bioisosteric replacement involves using onebioisostere to replace another with the expectation of maintaining orslightly modifying the biological activity of the first bioisostere. Thebioisosteres in this case are thus atoms or groups of atoms havingsimilar size, shape and electron density. Preferred bioisosteres ofesters, amides or carboxylic acids are compounds containing two sitesfor hydrogen bond acceptance. In one embodiment, the ester, amide orcarboxylic acid bioisostere is a 5-membered monocyclic heteroaryl ring,such as an optionally substituted 1H-imidazolyl, an optionallysubstituted oxazolyl, 1H-tetrazolyl, [1,2,4]triazolyl, or an optionallysubstituted [1,2,4]oxadiazolyl.

As used herein, the terms “subject”, “patient” and “animal”, are usedinterchangeably and include, but are not limited to, a cow, monkey,horse, sheep, pig, mini pig, chicken, turkey, quail, cat, dog, mouse,rat, rabbit, guinea pig and human. The preferred subject, patient oranimal is a human.

As used herein, the term “lower” refers to a group having up to fourcarbon atoms. For example, a “lower alkyl” refers to an alkyl radicalhaving from 1 to 4 carbon atoms, and a “lower alkenyl” or “loweralkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4carbon atoms, respectively. A lower alkoxy or a lower alkylsulfanylrefers to an alkoxy or an alkylsulfanyl having from 1 to 4 carbon atoms.Lower substituents are typically preferred.

Where a particular substituent, such as an alkyl substituent, occursmultiple times in a given structure or moeity, the identify of thesubstituted is independent in each case and may be the same as ordifferent from other occurrences of that substituent in the structure ormoiety. Furthermore, individual substituents in the specific embodimentsand exemplary compounds of this invention are preferred in combinationwith other such substituents in the compounds of this invention, even ifsuch individual substituents are not expressly noted as being preferredor not expressly shown in combination with other substituents.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

Suitable substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino,dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groupsinclude any substituent which will form a stable compound of theinvention. Examples of substituents for an alkyl, alkoxy, alkylsulfanyl,alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkylinclude an alkyl, an alkoxy, an alkylsulfanyl, an alkylamino, adialkylamino, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aheterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, ahaloalkyl, —C(O)NR₂₃R₂₄, —NR₂₅C(O)R₂₆, halo, —OR₂₅, cyano, nitro,haloalkoxy, —C(O)R₂₅, —NR₂₃R₂₄, —SR₂₅, —C(O)OR₂₅, —OC(O)R₂₅,—NR₂₅C(O)NR₂₃R₂₄, —OC(O)NR₂₃R₂₄, —NR₂₅C(O)OR₂₆, —S(O)_(p)R₂₅, or—S(O)_(p)NR₂₃R₂₄, wherein R₂₃ and R₂₄ for each occurrence are,independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl acycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or aheteraralkyl; or R₂₃ and R₂₄ taken together with the nitrogen to whichthey are attached is a heterocyclyl or a heteroaryl; and R₂₅ and R₂₆ foreach occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl,a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, anaralkyl, or a heteraralkyl;

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and anysaturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, andheteroaralkyl groups, may also be substituted with ═O, ═S, ═N—R₂₂.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent thenitrogen may be a quaternary nitrogen.

Choices and combinations of substituents and variables envisioned bythis invention are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject). Typically, such compounds arestable at a temperature of 40° C. or less, in the absence of excessivemoisture, for at least one week. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

Unless indicated otherwise, the compounds of the invention containingreactive functional groups (such as, without limitation, carboxy,hydroxy, and amino moieties) also include protected derivatives thereof.“Protected derivatives” are those compounds in which a reactive site orsites are blocked with one ore more protecting groups. Suitableprotecting groups for carboxy moieties include benzyl, tert-butyl, andthe like. Suitable protecting groups for amino and amido groups includeacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitableprotecting groups for hydroxy include benzyl, trimethyl silyl (TMS) andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981,the entire teachings of which are incorporated herein by reference.

As used herein, the term “compound(s) of this invention” and similarterms refers to a compound of any one of formulas (I) through (XIV), orTable 1, or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof and also include protected derivatives thereof.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may only become active upon suchreaction under biological conditions, but they may have activity intheir unreacted forms. Examples of prodrugs contemplated in thisinvention include, but are not limited to, analogs or derivatives ofcompounds of any one of formulas (I) through (XIV), or Table 1 thatcomprise biohydrolyzable moieties such as biohydrolyzable amides,biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, and biohydrolyzable phosphateanalogues. Other examples of prodrugs include derivatives of compoundsof any one of formulas (I) through (XIV), or of Table 1 that comprise—NO, —NO₂, —ONO, or —ONO₂ moieties. Prodrugs can typically be preparedusing well-known methods, such as those described by 1 BURGER'sMEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (ManfredE. Wolff ed., 5^(th) ed), the entire teachings of which are incorporatedherein by reference.

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide, or phosphate analogue, respectively, that either: 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as uptake,duration of action, or onset of action; or 2) is itself biologicallyinactive but is converted in vivo to a biologically active compound.Examples of biohydrolyzable amides include, but are not limited to,lower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroatomatic amines, andpolyether amines.

As used herein, the term “pharmaceutically acceptable salt,” is a saltformed from an acid and a basic group of one of the compounds of any oneof formulas (I) through (XIV) or of Table 1. Illustrative salts include,but are not limited, to sulfate, citrate, acetate, oxalate, chloride,bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from acompound of any one of formulas (I) through (XIV) or Table 1 having anacidic functional group, such as a carboxylic acid functional group, anda pharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)-amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)-amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of any one of formulas (I) through (XIV) orTable 1 having a basic functional group, such as an amino functionalgroup, and a pharmaceutically acceptable inorganic or organic acid.Suitable acids include, but are not limited to, hydrogen sulfate, citricacid, acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide,hydrogen iodide, nitric acid, phosphoric acid, isonicotinic acid, lacticacid, salicylic acid, tartaric acid, ascorbic acid, succinic acid,maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid,saccharic acid, formic acid, benzoic acid, glutamic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, andp-toluenesulfonic acid.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more solvent molecules toone or more molecules of a compound of any one of formulas (I) through(XIV) or Table 1. The term solvate includes hydrates (e.g.,hemi-hydrate, mono-hydrate, dihydrate, trihydrate, tetrahydrate, and thelike).

As used herein, the term “clathrate” means a compound of the presentinvention or a salt thereof in the form of a crystal lattice thatcontains spaces (e.g., channels) that have a guest molecule (e.g., asolvent or water) trapped within.

As used herein, the term “asthma” means a pulmonary disease, disorder orcondition characterized by reversible airway obstruction, airwayinflammation, and increased airway responsiveness to a variety ofstimuli.

“Immunosuppression” refers to impairment of any component of the immunesystem resulting in decreased immune function. This impairment may bemeasured by any conventional means including whole blood assays oflymphocyte function, detection of lymphocyte proliferation andassessment of the expression of T cell surface antigens. The antisheepred blood cell (SRBC) primary (IgM) antibody response assay (usuallyreferred to as the plaque assay) is one specific method. This and othermethods are described in Luster, M. I., Portier, C., Pait, D. G., White,K. L, Jr., Gennings, C., Munson, A. E., and Rosenthal, G. J. (1992),“Risk Assessment in Immunotoxicology I: Sensitivity and Predictabilityof Immune Tests,” Fundam. Appl. Toxicol., 18, 200-210. Measuring theimmune response to a T-cell dependent immunogen is another particularlyuseful assay (Dean, J. H., House, R. V., and Luster, M. I. (2001).“Immunotoxicology: Effects of, and Responses to, Drugs and Chemicals.”In Principles and Methods of Toxicology: Fourth Edition (A. W. Hayes,Ed.), pp. 1415-1450, Taylor & Francis, Philadelphia, Pa.).

The compounds of this invention can be used to treat subjects withimmune disorders. As used herein, the term “immune disorder” and liketerms means a disease, disorder or condition caused by the immune systemof an animal, including autoimmune disorders. Immune disorders includethose diseases, disorders or conditions that have an immune componentand those that are substantially or entirely immune system-mediated.Autoimmune disorders are those wherein the animal's own immune systemmistakenly attacks itself, thereby targeting the cells, tissues, and/ororgans of the animal's own body. For example, the autoimmune reaction isdirected against the nervous system in multiple sclerosis and the gut inCrohn's disease. In other autoimmune disorders such as systemic lupuserythematosus (lupus), affected tissues and organs may vary amongindividuals with the same disease. One person with lupus may haveaffected skin and joints whereas another may have affected skin, kidney,and lungs. Ultimately, damage to certain tissues by the immune systemmay be permanent, as with destruction of insulin-producing cells of thepancreas in Type 1 diabetes mellitus. Specific autoimmune disorders thatmay be ameliorated using the compounds and methods of this inventioninclude without limitation, autoimmune disorders of the nervous system(e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathiessuch as Guillain-Barré, and autoimmune uveitis), autoimmune disorders ofthe blood (e.g., autoimmune hemolytic anemia, pernicious anemia, andautoimmune thrombocytopenia), autoimmune disorders of the blood vessels(e.g., temporal arteritis, anti-phosphoilpid syndrome, vasculites suchas Wegener's granulomatosis, and Behcet's disease), autoimmune disordersof the skin (e.g., psoriasis, dermatitis herpetiformis, pemphigusvulgaris, and vitiligo), autoimmune disorders of the gastrointestinalsystem (e.g., Crohn's disease, ulcerative colitis, primary biliarycirrhosis, and autoimmune hepatitis), autoimmune disorders of theendocrine glands (e.g., Type 1 or immune-mediated diabetes mellitus,Grave's disease, Hashimoto's thyroiditis, autoimmune oophoritis andorchitis, and autoimmune disorder of the adrenal gland); and autoimmunedisorders of multiple organs (including connective tissue andmusculoskeletal system diseases) (e.g., rheumatoid arthritis, systemiclupus erythematosus, scleroderma, polymyositis, dermatomyositis,spondyloarthropathies such as ankylosing spondylitis, and Sjogren'ssyndrome). In addition, other immune system mediated diseases, such asgraft-versus-host disease and allergic disorders, are also included inthe definition of immune disorders herein. Because a number of immunedisorders are caused by inflammation, there is some overlap betweendisorders that are considered immune disorders and inflammatorydisorders. For the purpose of this invention, in the case of such anoverlapping disorder, it may be considered either an immune disorder oran inflammatory disorder. “Treatment of an immune disorder” hereinrefers to administering a compound or a composition of the invention toa subject, who has an immune disorder, a symptom of such a disease or apredisposition towards such a disease, with the purpose to cure,relieve, alter, affect, or prevent the autoimmune disorder, the symptomof if, or the predisposition towards it.

As used herein, the term “allergic disorder” means a disease, conditionor disorder associated with an allergic response against normallyinnocuous substances. These substances may be found in the environment(such as indoor air pollutants and aeroallergens) or they may benon-environmental (such as those causing dermatological or foodallergies). Allergens can enter the body through a number of routes,including by inhalation, ingestion, contact with the skin or injection(including by insect sting). Many allergic disorders are linked toatopy, a predisposition to generate the allergic antibody IgE. BecauseIgE is able to sensitize mast cells anywhere in the body, atopicindividuals often express disease in more than one organ. For thepurpose of this invention, allergic disorders include anyhypersensitivity that occurs upon re-exposure to the sensitizingallergen, which in turn causes the release of inflammatory mediators.Allergic disorders include without limitation, allergic rhinitis (e.g.,hay fever), sinusitis, rhinosinusitis, chronic or recurrent otitismedia, drug reactions, insect sting reactions, latex reactions,conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions,atopic dermatitis, asthma and food allergies.

The compounds of this invention can be used to prevent or to treatsubjects with inflammatory disorders. As used herein, an “inflammatorydisorder” means a disease, disorder or condition characterized byinflammation of body tissue or having an inflammatory component. Theseinclude local inflammatory responses and systemic inflammation. Examplesof such inflammatory disorders include: transplant rejection, includingskin graft rejection; chronic inflammatory disorders of the joints,including arthritis, rheumatoid arthritis, osteoarthritis and bonediseases associated with increased bone resorption; inflammatory boweldiseases such as ileitis, ulcerative colitis, Barrett's syndrome, andCrohn's disease; inflammatory lung disorders such as asthma, adultrespiratory distress syndrome, and chronic obstructive airway disease;inflammatory disorders of the eye including corneal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis;chronic inflammatory disorders of the gums, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney including uremic complications, glomerulonephritis and nephrosis;inflammatory disorders of the skin including sclerodermatitis, psoriasisand eczema; inflammatory diseases of the central nervous system,including chronic demyelinating diseases of the nervous system, multiplesclerosis, AIDS-related neurodegeneration and Alzheimer's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis and viral orautoimmune encephalitis; autoimmune disorders, immune-complexvasculitis, systemic lupus and erythematodes; systemic lupuserythematosus (SLE); and inflammatory diseases of the heart such ascardiomyopathy, ischemic heart disease hypercholesterolemia,atherosclerosis; as well as various other diseases with significantinflammatory components, including preeclampsia; chronic liver failure,brain and spinal cord trauma, and cancer. There may also be a systemicinflammation of the body, exemplified by gram-positive or gram negativeshock, hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to pro-inflammatory cytokines, e.g., shockassociated with pro-inflammatory cytokines. Such shock can be induced,e.g., by a chemotherapeutic agent used in cancer chemotherapy.“Treatment of an inflammatory disorder” herein refers to administering acompound or a composition of the invention to a subject, who has aninflammatory disorder, a symptom of such a disorder or a predispositiontowards such a disorder, with the purpose to cure, relieve, alter,affect, or prevent the inflammatory disorder, the symptom of it, or thepredisposition towards it.

An “effective amount” is the quantity of compound in which a beneficialoutcome is achieved when the compound is administered to a subject oralternatively, the quantity of compound that possess a desired activityin-vivo or in-vitro. In the case of inflammatory disorders andautoimmune disorders, a beneficial clinical outcome includes reductionin the extent or severity of the symptoms associated with the disease ordisorder and/or an increase in the longevity and/or quality of life ofthe subject compared with the absence of the treatment. The preciseamount of compound administered to a subject will depend on the type andseverity of the disease or condition and on the characteristics of thesubject, such as general health, age, sex, body weight and tolerance todrugs. It will also depend on the degree, severity and type ofinflammatory disorder, autoimmune disorder, allergic disorder, or thedegree of immunosuppression sought. The skilled artisan will be able todetermine appropriate dosages depending on these and other factors.Effective amounts of the disclosed compounds typically range betweenabout 1 mg/mm² per day and about 10 grams/mm² per day, and preferablybetween 10 mg/mm² per day and about 1 gram/mm².

The compounds of the invention may contain one or more chiral centersand/or double bonds and, therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to this invention, the chemical structuresdepicted herein, including the compounds of this invention, encompassall of the corresponding compounds' enantiomers and stereoisomers, thatis, both the stereomerically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and enantiomeric,diastereomeric, and geometric isomeric mixtures. In some cases, oneenantiomer, diastereomer, or geometric isomer will possess superioractivity or an improved toxicity or kinetic profile compared to others.In those cases, such enantiomers, diastereomers, and geometric isomersof a compound of this invention are preferred.

The term “inhibit production of IL-2” and like terms means inhibitingIL-2 synthesis (e.g. by inhibiting transcription (mRNA expression), ortranslation (protein expression)) and/or inhibiting IL-2 secretion in acell that has the ability to produce and/or secrete IL-2 (e.g., Tlymphocyte). Likewise, the term “inhibiting production of IL-4, IL-5,IL-13, GM-CSF, TNF-α or INF-γ means inhibiting the synthesis (e.g. byinhibiting transcription, or translation) and/or inhibiting thesecretion in a cell that has the ability to produce and/or secrete thesecytokines.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound.

As used herein, a composition that is “substantially free” of a compoundmeans that the composition contains less than about 20% by weight, morepreferably less than about 10% by weight, even more preferably less thanabout 5% by weight, and most preferably less than about 3% by weight ofthe compound.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct, more preferably more than about 90% by weight of the desiredproduct, even more preferably more than about 95% by weight of thedesired product, and most preferably more than about 97% by weight ofthe desired product.

As used herein, a racemic mixture means about 50% of one enantiomer andabout 50% of is corresponding enantiomer relative to all chiral centersin the molecule. The invention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds of any one of formulas(I) through (XIV) or Table 1.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

When administered to a patient, e.g., to a non-human animal forveterinary use or for improvement of livestock, or to a human forclinical use, the compounds of the invention are typically administeredin isolated form or as the isolated form in a pharmaceuticalcomposition. As used herein, “Isolated” means that the compounds of theinvention are separated from other components of either (a) a naturalsource, such as a plant or cell, preferably bacterial culture, or (b) asynthetic organic chemical reaction mixture. Preferably, viaconventional techniques, the compounds of the invention are purified. Asused herein, “purified” means that when isolated, the isolate containsat least 95%, preferably at least 98%, of a single compound of theinvention by weight of the isolate.

Only those choices and combinations of substituents that result in astable structure are contemplated. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

Specific Embodiments

The invention relates to compounds and pharmaceutical compositions thatare particularly useful for immunosuppression or to treat or preventinflammatory conditions, immune disorders, and allergic disorders.

In one embodiment the invention relates to compounds of formula, (I):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   L is a linker selected from the group consisting of —NRCH₂—,        —CH₂NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—, —C(S)—, —NR—C(S)—,        —CH(S)—NR—;    -   each Z is independently selected from the group consisting of a        lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower        alkyl sufanyl, cyano, nitro, or lower haloalkoxy;    -   R, for each occurrence is independently selected from —H, an        alkyl, —C(O)R₅, or —C(O)OR₅;    -   R₁ is an optionally substituted aryl or an optionally        substituted heteroaryl;    -   R₂ is an optionally substituted cycloalkyl, an optionally        substituted cycloalkenyl, an optionally substituted aryl, or an        optionally substituted heteroaryl;    -   R₅, for each occurrence, is independently, H, an alkyl, a        cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl,        or a heteraralkyl; and    -   n is 0, 1 or 2.

In another embodiment, the invention relates to compounds of formula(II):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein R, R₁, R₂, Z and n are defined as for formula (II).

In another embodiment, the invention relates to compounds of formula(III):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

-   -   X₁ is CH, CR₄, or N;    -   X₂ is CH, CR₃, or N;    -   R₃ and R₄, for each occurrence are, independently, a halo,        cyano, nitro, an alkyl, a haloalkyl, an alkoxy, alkylsulfanyl,        hydroxyl, a heteroaryl, —NH₂, alkylamino, dialkylamino, or        —C(O)R₆;    -   R₆, for each occurrence, is independently, H, an alkyl, a        cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl,        or a heteraralkyl, —OR₇, —SR₇, or —NR₇R₇;    -   R₇, for each occurrence, is independently, H, an alkyl, a        heteroalkyl, a cycloalkyl, a heterocyclyl, an aryl, a        heteroaryl, an aralkyl, or a heteraralkyl; and    -   q and t, for each occurrence are, independently, 0 or an integer        from 1 to 5.

In another embodiment, the invention relates to compounds of formula(IV):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₆ and X₇ are each, independently, CH or N;    -   R₈ and R₉ are each, independently, a halo, a lower alkyl, a        lower alkoxy, a haloalky, or a lower haloalkoxyl; and    -   R₁₀ and R₁₁, are each, independently, a halo, cyano, a lower        alkyl, a lower haloalkyl, a lower alkoxy, a lower haloalkoxy,        tetrazolyl, 1-alkyl-tetrazolyl, a lower alkylester, —C(O)NH₂,        furanyl, oxazolyl, oxadiazolyl, 3-alkyloxadiazolyl, or        tetrazolyl.

In another embodiment, the invention relates to compounds of formulaIV):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

-   -   R₁₂ is an aryl or a heteroaryl, wherein the aryl and heteroaryl        are optionally substituted with one or more substituent selected        from the group consisting of an optionally substituted alkyl, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted aralkyl, or an        optionally substituted heteraralkyl, a halo, cyano, nitro,        —OR₁₇, —SR₁₇, —S(O)R₁₇, —S(O)_(p)OR₁₇, —OS(O)_(p)R₁₇,        —OS(O)_(p)OR₁₇, —NR₁₇S(O)_(p)R₁₇, —S(O)_(p)NR₁₅R₁₆, —NR₁₅R₁₆,        —C(X₃)R₁₇, —C(X₃)OR₁₇, —C(X₃)SR₁₇, —C(X₃)NR₁₅R₁₆, —NR₁₇C(X₃)R₁₈,        —NR₁₇C(X₃)OR₁₈, —NR₁₇C(X₃)SR₁₈, —NR₁₇C(X₃)NR₁₅R₁₆, —OC(X₃)R₁₇,        —OC(X₃)OR₁₇, —OC(X₃)SR₁₇, —SC(X₃)OR₁₇, —SC(X₃)SR₁₇,        —OC(X₃)NR₁₅R₁₆, —SC(X₃)NR₁₅R₁₆, —P(X₄)(X₅R₁₇)₂,        —X₅P(X₄)(X₅R₁₇)₂, —P(X₄)(R₁₇)₂, —P(X₄)(R₁₇)(X₅R₁₇);    -   R₁₃ is a cycloalkyl, a cycloalkenyl, an aryl, or a heteroaryl,        wherein the cycloalkyl, cycloalkenyl, aryl, or heteroaryl are        optionally substituted with one or more substituents selected        from the group consisting of an optionally substituted alkyl, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted cycloalkenyl, an optionally substituted aryl, an        optionally substituted heteroaryl, an optionally substituted        aralkyl, or an optionally substituted heteraralkyl, a halo,        cyano, nitro, a haloalkyl, —OR₁₇, —SR₁₇, —S(O)_(p)R₁₇,        —S(O)_(p)OR₁₇, —OS(O)_(p)R₁₇, —OS(O)_(p)OR₁₇, —S(O)_(p)NR₁₅R₁₆,        —NR₁₅R₁₆, —C(X₃)R₁₇, —C(X₃)OR₁₇, —C(X₃)SR₁₇, —C(X₃)NR₁₅R₁₆,        —NR₁₇C(X₃)R₁₈, —NR₁₇C(X₃)OR₁₈, —NR₁₇C(X₃)SR₁₈,        —NR₁₇C(X₃)NR₁₅R₁₆, —OC(X₃)R₁₇, —OC(X₃)OR₁₇, —OC(X₃)SR₁₇,        —SC(X₃)OR₁₇, —SC(X₃)SR₁₇, —OC(X₃)NR₁₅R₁₆, —SC(X₃)NR₁₅R₁₆,        —P(X₄)(X₅R₁₇)₂, —X₅P(X₄)(X₅R₁₇)₂, —P(X₄)(R₁₇)₂,        —P(X₄)(R₁₇)(X₅R₁₇;    -   R₁₄, for each occurrence is independently selected from —H, an        alkyl, —C(O)R₂₀, or —C(O)OR₂₀;    -   R₁₅ and R₁₆, for each occurrence are, independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₁₅ and R₁₆ taken together with the nitrogen to which they        are attached are an optionally substituted heterocyclyl or        optionally substituted heteroaryl;    -   R₁₇ and R₁₈, for each occurrence are, independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₁₉, for each occurrence, is independently —H, a halo, an alkyl,        —OR₁₇, —NR₁₅R₁₆, —C(O)R₁₇, —C(O)OR₁₇, or —C(O)NR₁₅R₁₆;    -   R₂₀, for each occurrence, is independently, H or an alkyl;    -   X₃ is ═O, ═S, or ═N—R₁₉;    -   X₄ is ═O or ═S;    -   X₅ is —O— or —S—;    -   p is 1 or 2; and    -   Z and n are defined as for formula (I).

In another embodiment, the invention relates to compounds of formula(VI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein R, R₁, R₂, Z and n are defined as for formula (I).

In another embodiment, the invention relates to compounds of formula(VII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein X₁, X₂, R₃, R₄, q and t are defined as for formula(III).

In another embodiment, the invention relates to compounds of formula(VIII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein X₆, X₇, R₈, R₉, R₁₀ and R₁₁ are defined as for formula(IV).

In another embodiment, the invention relates to compounds of formula(IX):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

R₂₁ is an alkyl which is optionally substituted with one or moresubstituents selected from the group consisting of an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, a halo, cyano, nitro, a haloalkyl, —OR₁₇,—SR₁₇, —S(O)_(p)R₁₇, —S(O)_(p)OR₁₇, —OS(O)_(p)R₁₇, —OS(O)_(p)OR₁₇,—S(O)_(p)NR₁₅R₁₆, —NR₁₅R₁₆, —C(X₃)OR₁₇, —C(X₃)OR₁₇, —C(X₃)SR₁₇,—C(X₃)NR₁₅R₁₆, —NR₁₇C(X₃)R₁₈, —NR₁₇C(X₃)OR₁₈, —NR₁₇C(X₃)SR₁₈,—NR₁₇C(X₃)NR₁₅R₁₆, —OC(X₃)R₁₇, —OC(X₃OR₁₇, —OC(X₃)SR₁₇, —SC(X₃)OR₁₇,—SC(X₃)R₁₇, —OC(X₃)NR₁₅R₁₆, —SC(X₃)NR₁₅R₁₆, —P(X₄)(X₅R₁₇)₂,—X₅P(X₄R₁₇)₂, —P(X₄)(R₁₇)₂, —P(X₄)(X₅R₁₇);

-   -   R₁, Z and n are defined as for formula (I); and    -   R₁₅, R₁₆, R₁₇, R₁₈, X₃, X₄, X₅, and p are defined as for formula        (V).

In another embodiment, the invention relates to compounds of formula(X):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

-   -   R, R₁, Z, and n are defined as for formula (I); and    -   R₂₁ is defined as for formula (IX).

In another embodiment, the invention relates to compounds of formula(XI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

-   -   X₆, R₁₀ and R₁₁ are defined as for formula (IV); and    -   R₂₁ is defined as for formula (IX).

In another embodiment, the invention relates to compounds of formula(XII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

-   -   X₈ and X₉ are N and X₁₀ and X₁₁ are CH or CZ; or X₁₀ and X₁₁ are        N and X₈ and X₉ are CH or CZ;    -   L, Z, R₁, and R₂ are defined as for formula (I).

In another embodiment, the invention relates to compounds of formula(XIII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

-   -   X₈, X₉, X₁₀ and X₁₁ are defined as for formula (XII); and    -   R, R₁, and R₂ are defined as for formula (I).

In another embodiment, the invention relates to compounds of formula(XIV):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

-   -   X₈, X₉, X₁₀ and X₁₁ are defined as for formula (XII);    -   R₂ are defined as for formula (I); and    -   X₆, R₁₀ and R₁₁ are defined as for formula (IV).

In one embodiment, in the compounds represented by formula (I), (IX), or(XII), L is —NH—C(O)— or —C(O)—NH—.

In another embodiment, in the compounds represented by formula (I),(IX), or (XII), L is —NH—CH₂— or —CH₂—NH—.

In another embodiment, in the compounds represented by formula (I),(II), (V), (VI), (IX), or (X), n is 0.

In another embodiment, in the compounds represented by formula (I),(II), (V), (VI), (IX), or (X), n is 1. In one aspect of this embodiment,Z is a halo.

In another embodiment, in the compounds represented by formula (I),(II), (V), (VI), (IX), or (X), n is 2. In one aspect of this embodiment,Z, for each occurrence, is, independently, a halo.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (IX), (X), (XII), or (XIII, R is H.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (IX), (X), (XII), or (XIII), R is a lower alkyl, such asmethyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (IX), (X), (XII), or (XIII), R, is selected from the groupconsisting of an optionally substituted phenyl, an optionallysubstituted naphthyl, an optionally substituted anthracenyl anoptionally substituted pyridyl, an optionally substituted furyl, anoptionally substituted thienyl, an optionally substituted pyrrolyl, anoptionally substituted oxazolyl, an optionally substituted imidazolyl,an optionally substituted indolizinyl, an optionally substitutedthiazolyl, an optionally substituted isoxazolyl, an optionallysubstituted pyrazolyl, an optionally substituted isothiazolyl, anoptionally substituted pyridazinyl, an optionally substitutedpyrimidinyl, an optionally substituted pyrazinyl, an optionallysubstituted triazinyl, an optionally substituted triazolyl, anoptionally substituted thiadiazolyl, an optionally substitutedpyrazinyl, an optionally substituted quinolinyl, an optionallysubstituted isoquinolinyl, an optionally substituted indazolyl, anoptionally substituted benzoxazolyl, an optionally substitutedbenzofuryl, an optionally substituted benzothiazolyl, an optionallysubstituted indolizinyl, an optionally substituted imidazopyridinyl, anoptionally substituted isothiazolyl, an optionally substitutedtetrazolyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzothiazolyl, an optionally substituted benzothiadiazolyl,an optionally substituted benzoxadiazolyl, an optionally substitutedindolyl, an optionally substituted tetrahydroindolyl, an optionallysubstituted azaindolyl, an optionally substituted imidazopyridyl, anoptionally substituted quinazolinyl, an optionally substituted purinyl,an optionally substituted pyrrolo[2,3]pyrimidyl, an optionallysubstituted pyridopyrimidyl, an optionally substitutedpyrazolo[3,4]pyrimidyl or an optionally substituted benzo(b)thienyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (IX), (X), (XII), or (XIII), R₁ is an optionally substitutedphenyl or an optionally substituted 5-membered heteroaryl. In one aspectof this embodiment, is an optionally substituted 5-membered heteroaryl.Examples of optionally substituted 5-membered heteroaryl groups includean optionally substituted furyl, an optionally substituted thienyl, anoptionally substituted pyrrolyl, an optionally substituted oxazolyl, anoptionally substituted imidazolyl, an optionally substituted thiazolyl,an optionally substituted isoxazolyl, an optionally substitutedpyrazolyl, an optionally substituted isothiazolyl, an optionallysubstituted pyrazinyl, an optionally substituted triazinyl, anoptionally substituted triazolyl, an optionally substitutedthiadiazolyl, and an optionally substituted tetrazolyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (IX), (X), (XII), or (XIII), R₁ is an optionally substitutedphenyl or an optionally substituted 6-membered heteroaryl. In one aspectof this embodiment, R₁ is an optionally substituted 6-memberedheteroaryl. Examples of optionally substituted 6-membered heteroarylgroups include an optionally substituted pyridyl, an optionallysubstituted pyridazinyl, an optionally substituted pyrimidinyl, anoptionally substituted pyrazinyl, or an optionally substitutedtriazinyl. In another aspect of this embodiment, R₁ is unsubstituted. Inanother aspect of this embodiment, R₁ is substituted with onesubstituent, for example, R₁ is substituted with a substituent that isortho to its point of attachment to the pyrazine or pyridazine ring. Inanother aspect of this embodiment, R₁ is substituted with twosubstituent, for example R₁ is substituted with one substituent that isortho to its point of attachment to the pyrazine or pyridazine ring, andanother substituent that is para to the first substituent.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (IX), (X), (XII), or (XIII), R₁ is an optionally substitutedheteroaryl selected from the group consisting of an optionallysubstituted indolizinyl, an optionally substituted quinolinyl, anoptionally substituted isoquniolinyl, an optionally substitutedindazolyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzofuryl, an optionally substituted benzothiazolyl, anoptionally substituted indolizinyl, an optionally substitutedimidazopyridinyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzothiazolyl, an optionally substituted benzothiadiazolyl,an optionally substituted benzoxadiazolyl, an optionally substitutedindolyl, an optionally substituted tetrahydroindolyl, an optionallysubstituted azaindolyl, an optionally substituted imidazopyridyl, anoptionally substituted quinazolinyl, an optionally substituted purinyl,an optionally substituted pyrrolo[2,3]pyrimidyl, an optionallysubstituted pyridopyrimidyl, an optionally substitutedpyrazolo[3,4]pyrimidyl or an optionally substituted benzo(b)thienyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (IX), (X), (XII), or (XIII), R₁ is an optionally substitutedphenyl, an optionally substituted tetrazolyl, or an optionallysubstituted pyridinyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (IX), (X), (XII), or (XIII), R₁ is an optionally substitutedphenyl or an optionally substituted pyridinyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (IX), (X), (XII), or (XIII), R₁ is substituted with one ormore substituents selected from the group consisting of an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, or anoptionally substituted heteraralkyl, a halo, cyano, nitro, a haloalkyl,—OR₁₇, —SR₁₇, —S(O)_(p)R₁₇, —S(O)_(p)OR₁₇, —OS(O)_(p)R₁₇,—OS(O)_(p)OR₁₇, —S(O)_(p)NR₁₅R₁₆, —NR₁₅R₁₆, —C(X₃)R₁₇, —C(X₃)OR₁₇,—C(X₃)SR₁₇, —C(X₃)NR₁₅R₁₆, —NR₁₇C(X₃)R₁₈, —NR₁₇C(X₃)OR₁₈,—NR₁₇C(X₃)SR₁₈, —NR₁₇C(X₃)NR₁₅R₁₆, —OC(X₃)R₁₇, —OC(X₃)OR₁₇, —OC(X₃)SR₁₇,—SC(X₃)OR₁₇, —SC(X₃)SR₁₇, —OC(X₃)NR₁₅R₁₆, —SC(X₃)NR₁₅R₁₆,—P(X₄)(X₅R₁₇)₂, —X₅P(X₄)(X₅R₁₇)₂, —P(X₄)(R₁₇)₂, —P(X₄)(R₁₇)(X₅R₁₇;wherein R₁₅, R₁₆, R₁₇, R₁₈, X₃, X₄, X₅, and p are defined as above.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (IX), (X), (XII), or (XIII), R₁ is substituted with one ormore substituents selected from the group consisting of a lower alkyl, ahalo, cyano, nitro, a lower haloalkyl, a lower alkoxy, a lowersulfanylalkyl, —S(O)_(p)R₃₁, —S(O)_(p)NR₂₉R₃₀, —NR₂₉R₃₀, —C(O)R₂₈,—C(O)OR₂₈, —C(O)NR₂₉R₃₀, —NR₂₉C(O)R₃₀, —NR₂₉C(O)OR₂₈, —NR₂₈C(O)NR₂₉R₃₀,—OC(O)R₂₈, —OC(O)OR₂₈, and —OC(O)NR₂₉R₃₀; wherein p is defined as above;R₂₈, R₂₉, R₃₀, for each occurrence are, independently, H or a loweralkyl; and R₃₁, for each occurrence, is independently a lower alkyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (IX), (X), (XII), or (XIII), R₁ is substituted with one ormore substituents selected from the group consisting of a halo, a loweralkyl, a lower haloalkyl, a lower alkoxy, a 5-membered heteroaryl (e.g.tetrazol-5-yl, 1-methyl-tetrazol-5-yl, furan-2-yl, furan-3-yl,oxazol-2-yl, and 3-methyl-[1,2,4]oxadiazol-5-yl), —C(O)H, —C(O)OR₂₆,—C(O)R₂₈, and —C(O)NR₂₉R₃₀; wherein R₂₈, R₂₉, R₃₀, for each occurrenceare, independently, H or a lower alkyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (XII), (XIII), or (XIV), R₂ is an optionally substitutedaryl or an optionally substituted heteroaryl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (XII), (XIII), or (XIV), R₂ is an optionally substitutedphenyl or an optionally substituted 5-membered heteroaryl. In one aspectof this embodiment, R₂ is an optionally substituted 5-memberedheteroaryl. Examples of optionally substituted 5-membered heteroarylgroups include an optionally substituted furyl, an optionallysubstituted thienyl, an optionally substituted pyrrolyl, an optionallysubstituted oxazolyl, an optionally substituted imidazolyl, anoptionally substituted thiazolyl, an optionally substituted isoxazolyl,an optionally substituted pyrazolyl, an optionally substitutedisothiazolyl, an optionally substituted pyrazinyl, an optionallysubstituted triazinyl, an optionally substituted triazolyl, anoptionally substituted thiadiazolyl, and an optionally substitutedtetrazolyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (XII), (XIII), or (XIV), R₂ is an optionally substitutedphenyl or an optionally substituted 6-membered heteroaryl. In one aspectof this embodiment, R₂ is an optionally substituted 6-memberedheteroaryl. Examples of optionally substituted 6-membered heteroarylgroups include an optionally substituted pyridyl, an optionallysubstituted pyridazinyl, an optionally substituted pyrimidinyl, anoptionally substituted pyrazinyl, or an optionally substitutedtriazinyl. In another aspect of this embodiment, R₂ is unsubstituted. Inanother aspect of this embodiment, R₂ is substituted with onesubstituent, for example, R₂ is substituted with a substituent that isortho to its point of attachment to L or —NR—C(O)—. In another aspect ofthis embodiment, R₂ is substituted with two substituent, for example, R₂is substituted with two substituent that are ortho to its point ofattachment to L or —NR—C(O)—.

In another embodiment in the compounds represented by formula (I), (II),(VI), (XII), (XIII), or (XIV), R₂ is an optionally substitutedheteroaryl selected from the group consisting of an optionallysubstituted indolizinyl, an optionally substituted quinolinyl, anoptionally substituted isoquinolinyl, an optionally substitutedindazolyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzofuryl, an optionally substituted benzothiazolyl, anoptionally substituted indolizinyl, an optionally substitutedimidazopyridinyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzothiazolyl, an optionally substituted benzothiadiazolyl,an optionally substituted benzoxadiazolyl, an optionally substitutedindolyl, an optionally substituted tetrahydroindolyl, an optionallysubstituted azaindolyl, an optionally substituted imidazopyridyl, anoptionally substituted quinazolinyl, an optionally substituted purinyl,an optionally substituted pyrrolo[2,3]pyrimidyl, an optionallysubstituted pyridopyrimidyl, an optionally substitutedpyrazolo[3,4]pyrimidyl or an optionally substituted benzo(b)thienyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (XII), (XIII), or (XIV), R₂ is an optionally substitutedphenyl or an optionally substituted pyridinyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (XII), (XIII), or (XIV), R₂ an optionally substitutedcycloalkyl or an optionally substituted cycloalkenyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (XII), (XIII), or (XIV), R₂ is substituted with one or moresubstituents selected from the group consisting of an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, or anoptionally substituted heteraralkyl, a halo, cyano, nitro, a haloalkyl,—OR₁₇, —SR₁₇, —S(O)_(p)R₁₇, —S(O)_(p)OR₁₇, —OS(O)_(p)R₁₇,—OS(O)_(p)OR₁₇, —S(O)_(p)NR₁₅R₁₆, —NR₁₅R₁₆, —C(X₃)R₁₇, —C(X₃)OR₁₇,—C(X₃)SR₁₇, —C(X₃)NR₁₅R₁₆, —NR₁₇C(X₃)R₁₈, —NR₁₇C(X₃)OR₁₈,—NR₁₇C(X₃)SR₁₈, —NR₁₇C(X₃)NR₁₅R₁₆, —OC(X₃)R₁₇, —OC(X₃)OR₁₇, —OC(X₃)SR₁₇,—SC(X₃)OR₁₇, —SC(X₃)SR₁₇, —OC(X₃)NR₁₅R₁₆, —SC(X₃)NR₁₅R₁₆,—P(X₄)(X₅R₁₇)₂, —X₅P(X₄)(X₅R₁₇)₂, —P(X₄)(R₁₇)₂, —P(X₄)(R₁₇)(X₅R₁₇;wherein R₁₅, R₁₆, R₁₇, R₁₈, X₃, X₄, X₅, and p are defined as above.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (XII), (XIII), or (XIV), R₂ is substituted with one or moresubstituents selected from the group consisting of a lower alkyl, ahalo, cyano, nitro, a lower haloalkyl, a lower alkoxy, a lowersulfanylalkyl, —S(O)_(p)R₃₁, —S(O)_(p)NR₂₉R₃₀, —NR₂₉R₃₀, —C(O)R₂₈,—C(O)OR₂₈, —C(O)NR₂₉R₃₀, —NR₂₉C(O)R₃₀, —NR₂₉C(O)OR₂₈, —NR₂₈C(O)NR₂₉R₃₀,—OC(O)R₂₈, —OC(O)OR₂₈, and —OC(O)NR₂₉R₃₀; wherein p is defined as above;R₂₈, R₂₉, R₃₀, for each occurrence are, independently, H or a loweralkyl; and R₃₁, for each occurrence, is independently a lower alkyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (XII), (XIII), or (XIV), R₂ is substituted with one or moresubstituents selected from the group consisting of a halo or a loweralkyl.

In another embodiment, in the compounds represented by formula (I),(II), (VI), (XII), (XIII), or (XIV), R₂ is 2,6-difluorophenyl,3-fluoropyridin-4-yl, or 3-methy-pyridin-4-yl.

In another embodiment, in the compounds represented by formula (V), R₁₄is H.

In another embodiment, in the compounds represented by formula (V), R₁₄is a lower alkyl, such as methyl.

In another embodiment, in the compounds represented by formula (V), R₁₂is selected from the group consisting of an optionally substitutedphenyl, an optionally substituted naphthyl, an optionally substitutedanthracenyl, an optionally substituted pyridyl, an optionallysubstituted furyl, an optionally substituted thienyl, an optionallysubstituted pyrrolyl, an optionally substituted oxazolyl, an optionallysubstituted imidazolyl, an optionally substituted indolizinyl, anoptionally substituted thiazolyl, an optionally substituted isoxazolyl,an optionally substituted pyrazolyl, an optionally substitutedisothiazolyl, an optionally substituted pyridazinyl, an optionallysubstituted pyrimidinyl, an optionally substituted pyrazinyl, anoptionally substituted triazinyl, an optionally substituted triazolyl,an optionally substituted thiadiazolyl, an optionally substitutedpyrazinyl, an optionally substituted quinolinyl, an optionallysubstituted isoquniolinyl, an optionally substituted indazolyl, anoptionally substituted benzoxazolyl, an optionally substitutedbenzofuryl, an optionally substituted benzothiazolyl, an optionallysubstituted indolizinyl, an optionally substituted imidazopyridinyl anoptionally substituted isothiazolyl, an optionally substitutedtetrazolyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzothiaxolyl, an optionally substituted benzothiadiazolyl,an optionally substituted benzoxadiazolyl, an optionally substitutedindolyl, an optionally substituted tetrahydroindolyl, an optionallysubstituted azaindolyl, an optionally substituted imidazopyridyl, anoptionally substituted quinazolinyl, an optionally substituted purinyl,an optionally substituted pyrrolo[2,3]pyrimidyl, an optionallysubstituted pyridopyrimidyl, an optionally substitutedpyrazolo[3,4]pyrimidyl or an optionally substituted benzo(b)thienyl.

In another embodiment, in the compounds represented by formula (V), R₁₂is an optionally substituted phenyl or an optionally substituted5-membered heteroaryl. In one aspect of this embodiment, R₁₂ is anoptionally substituted 5-membered heteroaryl. Examples of optionallysubstituted 5-membered heteroaryl groups include an optionallysubstituted furyl, an optionally substituted thienyl, an optionallysubstituted pyrrolyl, an optionally substituted oxazolyl, an optionallysubstituted imidazolyl, an optionally substituted thiazolyl, anoptionally substituted isoxazolyl, an optionally substituted pyrazolyl,an optionally substituted isothiazolyl, an optionally substitutedpyrazinyl, an optionally substituted triazinyl, an optionallysubstituted triazolyl, an optionally substituted thiadiazolyl, and anoptionally substituted tetrazolyl.

In another embodiment, in the compounds represented by formula (V), R₁₂is an optionally substituted phenyl or an optionally substituted6-membered heteroaryl. In one aspect of this embodiment, R₁₂ is anoptionally substituted 6-membered heteroaryl. Examples of optionallysubstituted 6-membered heteroaryl groups include an optionallysubstituted pyridyl, an optionally substituted pyridazinyl, anoptionally substituted pyrimidinyl, an optionally substituted pyrazinyl,or an optionally substituted triazinyl. In another aspect of thisembodiment, R₁₂ is unsubstituted. In another aspect of this embodiment,R₁₂ is substituted with one substituent, for example, R₁₂ is substitutedwith a substituent that is ortho to its point of attachment to thepyrazine or pyridazine ring. In another aspect of this embodiment, R₁₂is substituted with two substituent, for example R₁₂ is substituted withone substituent that is ortho to its point of attachment to the pyrazineor pyridazine ring, and another substituent that is para to the firstsubstituent.

In another embodiment, in the compounds represented by formula (V), R₁₂is an optionally substituted heteroaryl selected from the groupconsisting of an optionally substituted iodolizinyl, an optionallysubstituted quinolinyl, an optionally substituted isoquniolinyl, anoptionally substituted indazolyl, an optionally substitutedbenzoxazolyl, an optionally substituted benzofuryl, an optionallysubstituted benzothiazolyl an optionally substituted indolizinyl, anoptionally substituted imidazopyridinyl, an optionally substitutedbenzoxazolyl, an optionally substituted benzothiazolyl, an optionallysubstituted benzothiadiazolyl, an optionally substitutedbenzoxadiazolyl, an optionally substituted indolyl, an optionallysubstituted tetrahydroindolyl, an optionally substituted azaindolyl, anoptionally substituted imidazopyridyl, an optionally substitutedquinazolinyl, an optionally substituted purinyl, an optionallysubstituted pyrrolo[2,3]pyrimidyl, an optionally substitutedpyridopyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl or anoptionally substituted benzo(b)thienyl.

In another embodiment, in the compounds represented by formula (V) R₁₂is an optionally substituted phenyl, an optionally substitutedtetrazolyl, or an optionally substituted pyridinyl.

In another embodiment, in the compounds represented by formula (V), R₁₂is an optionally substituted phenyl or an optionally substitutedpyridinyl.

In another embodiment, in the compounds represented by formula (I),(II), or (VI), R₁₂ is substituted with one or more substituents selectedfrom the group consisting of a lower alkyl, a halo, cyano, nitro, alower haloalkyl, a lower alkoxy, a lower sulfanylalkyl, —S(O)_(p)R₃₁,—S(O)_(p)NR₂₉R₃₀, —NR₂₉R₃₀, —C(O)R₂₈, —C(O)OR₂₈, —C(O)NR₂₉R₃₀,—NR₂₉C(O)R₃₀, —NR₂₉C(O)OR₂₈, —NR₂₈C(O)NR₂₉R₃₀, —OC(O)R₂₈, —OC(O)OR₂₈,and —OC(O)NR₂₉R₃₀; wherein p is defined as above; R₂₈, R₂₉, R₃₀, foreach occurrence are, independently, H or a lower alkyl; and R₃₁, foreach occurrence, is independently a lower alkyl.

In another embodiment, in the compounds represented by formula (V), R₁₂is substituted with one or more substituents selected from the groupconsisting of a halo, a lower alkyl, a lower haloalkyl, a lower alkoxy,a 5-membered heteroaryl (e.g., tetrazol-5-yl, 1-methyl-tetrazol-5-yl,furan-2-yl, furan-3-yl, oxazol-2-yl, and3-methyl-[1,2,4]oxadiazol-5-yl), —C(O)H, —C(O)OR₂₈, —C(O)R₂₈, and—C(O)NR₂₉R₃₀; wherein R₂₈, R₂₉, R₃₀, for each occurrence are,independently, H or a lower alkyl.

In another embodiment, in the compounds represented by formula (V), R₁₃is an optionally substituted aryl or an optionally substitutedheteroaryl.

In another embodiment, in the compounds represented by formula (V), R₁₃is an optionally substituted phenyl or an optionally substituted5-membered heteroaryl. In one aspect, of this embodiment, R₁₃ is anoptionally substituted 5-membered heteroaryl. Examples of optionallysubstituted 5-membered heteroaryl groups include an optionallysubstituted furyl, an optionally substituted thienyl, an optionallysubstituted pyrrolyl, an optionally substituted oxazolyl, an optionallysubstituted imidazolyl, an optionally substituted thiazolyl, anoptionally substituted isoxazolyl, an optionally substituted pyrazolyl,an optionally substituted isothiazolyl, an optionally substitutedpyrazinyl, an optionally substituted triazinyl, an optionallysubstituted triazolyl, an optionally substituted thiadiazolyl, and anoptionally substituted tetrazolyl.

In another embodiment, in the compounds represented by formula (V), R₁₃is an optionally substituted phenyl or an optionally substituted6-membered heteroaryl. In one aspect of this embodiment, R₁₃ is anoptionally substituted 6-membered heteroaryl. Examples of optionallysubstituted 6-membered heteroaryl groups include an optionallysubstituted pyridyl, an optionally substituted pyridazinyl, anoptionally substituted pyrimidinyl, an optionally substituted pyrazinyl,or an optionally substituted triazinyl. In another aspect of thisembodiment, R₁₃ is unsubstituted. In another aspect of this embodiment,R₁₃ is substituted with one substituent, for example, R₁₃ is substitutedwith a substituent that is ortho to its point of attachment to L or—NR—C(O)—. In another aspect of this embodiment, R₁₃ is substituted withtwo substituent, for example, R₁₃ is substituted with two substituentthat are ortho to its point of attachment to L or —NR—C(O)—.

In another embodiment, in the compounds represented by formula (V), R₁₃is an optionally substituted heteroaryl selected from the groupconsisting of an optionally substituted indolizinyl, an optionallysubstituted quinolinyl, an optionally substituted isoquniolinyl, anoptionally substituted indazolyl, an optionally substitutedbenzoxazolyl, an optionally substituted benzofuryl, an optionallysubstituted benzothiazolyl, an optionally substituted indolizinyl, anoptionally substituted imidazopyridinyl, an optionally substitutedbenzoxazolyl, an optionally substituted benzothiazolyl, an optionallysubstituted benzothiadiazolyl, an optionally substitutedbenzoxadiazolyl, an optionally substituted indolyl, an optionallysubstituted tetrahydroindolyl, an optionally substituted azaindolyl anoptionally substituted imidazopyridyl, an optionally substitutedquinazolinyl, an optionally substituted purinyl, an optionallysubstituted pyrrolo[2,3]pyrimidyl, an optionally substitutedpyridopyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl or anoptionally substituted benzo(b)thienyl.

In another embodiment, in the compounds represented by formula (V), R₁₃is an optionally substituted phenyl or an optionally substitutedpyridinyl.

In another embodiment, in the compounds represented by formula (V), R₁₃is an optionally substituted cycloalkyl or an optionally substitutedcycloalkenyl.

In another embodiment, in the compounds represented by formula (V), R₁₃is substituted with one or more substituents selected from the groupconsisting of a lower alkyl, a halo, cyano, nitro, a lower haloalkyl, alower alkoxy, a lower sulfanylalkyl, —S(O)_(p)R₃₁, —S(O)_(p)NR₂₉R₃₀,—NR₂₉R₃₀, —C(O)R₂₈, —C(O)OR₂₈, —C(O)NR₂₉R₃₀, —NR₂₉C(O)R₃₀,—NR₂₉C(O)OR₂₈, —NR₂₈C(O)NR₂₉R₃₀, —OC(O)R₂₈, —OC(O)OR₂₈, and—OC(O)NR₂₉R₃₀; wherein p is defined as above; R₂₈, R₂₉, R₃₀, for eachoccurrence are, independently, H or a lower alkyl; and R₃₁, for eachoccurrence, is independently a lower alkyl.

In another embodiment, in the compounds represented by formula (V), R₁₃is substituted with one or more substituents selected from the groupconsisting of a halo or a lower alkyl.

In another embodiment, in the compounds represented by formula (V), R₁₃is 2,6-difluorophenyl, 3-fluoropyridin-4-yl, or 3-methyl-pyridin-4-yl.

In another embodiment, in the compounds represented by formula (III) or(VII), X₁ and X₂ are CH.

In another embodiment, in the compounds represented by formula (III) or(VII), X₁ and X₂ are N.

In another embodiment, in the compounds represented by formula (III) or(VII), X₁ is CH and X₂ is N.

In another embodiment, in the compounds represented by formula (III) or(VII), X₁ is N and X₂ are CH.

In another embodiment, in the compounds represented by formula (III) or(VII), q is zero.

In another embodiment, in the compounds represented by formula (III) or(VII), q is 1.

In another embodiment, in the compounds represented by formula (III) or(VII), q is 2.

In another embodiment, in the compounds represented by formula (III) or(VII), t is zero.

In another embodiment, in the compounds represented by formula (III) or(VII), t is 1.

In another embodiment, in the compounds represented by formula (III) or(VII), t is 2.

In another embodiment, in the compounds represented by formula (III) or(VII), q is 1 and R₄ is a halo, a lower alkyl, a lower haloalkyl, alower alkoxy, a 5-membered heteroaryl (e.g., tetrazol-5-yl,1-methyl-tetrazol-5-yl, furan-2-yl, furan-3-yl, oxazol-2-yl, and3-methyl-[1,2,4]oxadiazol-5-yl), —C(O)H, —C(O)OR₂₈, —C(O)R₂₈, and—C(O)NR₂₉R₃₀; wherein R₂₈, R₂₉, R₃₀, for each occurrence are,independently, H or a lower alkyl.

In another embodiment, in the compounds represented by formula (III) or(VII), q is 2 and R₄, for each occurrence, is independently, a halo, alower alkyl, a lower haloalkyl, a lower alkoxy, a 5-membered heteroaryl(e.g., tetrazol-5-yl, 1-methyl-tetrazol-5-yl, furan-2-yl, furan-3-yl,oxazol-2-yl, and 3-methyl-[1,2,4]oxadiazol-5-yl), —C(O)H, —C(O)OR₂₈,—C(O)R₂₈, and —C(O)NR₂₉R₃₀; wherein R₂₈, R₂₉, R₃₀, for each occurrenceare, independently, H or a lower alkyl.

In another embodiment, in the compounds represented by formula (III) or(VII), t is 1 and R₃ is a halo, a lower alkyl, a lower haloalkyl, alower alkoxy, a 5-membered heteroaryl (e.g., tetrazol-5-yl,1-methyl-tetrazol-5-yl, furan-2-yl, furan-3-yl, oxazol-2-yl, and3-methyl-[1,2,4]oxadiazol-5-yl), —C(O)H, —C(O)OR₂₈, —C(O)R₂₈, and—C(O)NR₂₉R₃₀; wherein R₂₈, R₂₉, R₃₀, for each occurrence are,independently, H or a lower alkyl. In one aspect of this embodiment, R₃is ortho to the point of attachment to the pyrazine or pyridazine ring.

In another embodiment, in the compounds represented by formula (III or(VII), t is 1 and R₃ is a halo or a lower alkyl. In one aspect of thisembodiment, R₃ is ortho to the point of attachment to the pyrazine orpyridazine ring.

In another embodiment, in the compounds represented by formula (III) or(VII), t is 2 and R₃, for each occurrence, is, independently, a halo, alower alkyl, a lower haloalkyl, a lower alkoxy, a 5-membered heteroaryl(e.g., tetrazol-5-yl, 1-methyl-tetrazol-5-yl, furan-2-yl, furan-3-yl,oxazol-2-yl, and 3-methyl-[1,2,4]oxadiazol-5-yl), —C(O)H, —C(O)OR₂₈,—C(O)R₂₈, and —C(O)NR₂₉R₃₀; wherein R₂₈, R₂₉, R₃₀, for each occurrenceare, independently, H or a lower alkyl. In one aspect of thisembodiment, both R₃ groups are ortho to the point of attachment to thepyrazine or pyridazine ring.

In another embodiment, in the compounds represented by formula (III) or(VII), t is 2 and R₃, for each occurrence, is, independently, a halo ora lower alkyl. In one aspect of this embodiment, both R₃ groups areortho to the point of attachment to the pyrazine or pyridazine ring.

In another embodiment, in the compounds represented by formula (III) or(VII), q is 1 and R₄ is a halo, a lower alkyl, a lower haloalkyl, alower alkoxy, a 5-membered heteroaryl (e.g., tetrazol-5-yl,1-methyl-tetrazol-5-yl, furan-2-yl, furan-3-yl, oxazol-2-yl, and3-methyl-[1,2,4]oxadiazol-5-yl), —C(O)H, —C(O)OR₂₈, —C(O)R₂₈, and—C(O)NR₂₉R₃₀; wherein R₂₈, R₂₉, R₃₀, for each occurrence are,independently, H or a lower alkyl. In one aspect of this embodiment, R₄is ortho to the point of attachment to the pyrazine or pyridazine ring.

In another embodiment, in the compounds represented by formula (III) or(VII), q is 2 and R₄ is a halo, a lower alkyl, a lower haloalkyl, alower alkoxy, a 5-membered heteroaryl (e.g., tetrazol-5-yl,1-methyl-tetrazol-5-yl, furan-2-yl, furan-3-yl, oxazol-2-yl, and3-methyl-[1,2,4]oxadiazol-5-yl), —C(O)H, —C(O)OR₂₈, —C(O)R₂₈, and—C(O)NR₂₉R₃₀; wherein R₂₈, R₂₉, R₃₀, for each occurrence are,independently, H or a lower alkyl. In one aspect of this embodiment, thetwo R₄ groups are para to each other.

In another embodiment, in the compounds represented by formula (IV) or(VIII), X₆ and X₇ are CH.

In another embodiment, in the compounds represented by formula (XI), or(XIV), X₆ is CH.

In another embodiment, in the compounds represented by formula (IV) or(VIII), X₆ and X₇ are N.

In another embodiment, in the compounds represented by formula (XI), or(XIV), X₆ is N.

In another embodiment, in the compounds represented by formula (IV) or(VIII), X₆ is CH and X₇ is N.

In another embodiment, in the compounds represented by formula (IV) or(VIII), X₆ is N and X₇ are CH.

In another embodiment, in the compounds represented by formula (IV) or(VIII), R₈ and R₉ are each, independently, a halo or a lower alkyl.

In another embodiment, in the compounds represented by formula (IV) or(VIII), R₈ and R₉ are each fluoro.

In another embodiment, in the compounds represented by formula (IV),(VIII), (XI), or (XIV), R₁₀ and R₁₁ are each, independently, a halo,cyano, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —OCH₃, —CF₃, tetrazol-5-yl,1-methyl-tetrazol-5-yl, —C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)OCH₂CH₂CH₃,—C(O)NH₂, furan-2-yl, furan-3-yl, oxazol-2-yl, [1,2,4]oxadiazol-5-yl,3-methy-oxadiazol-5-yl, or tetrazol-5-yl.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-2,6-difluoro-benzamide;-   N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide;-   N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-2,6-difluoro-benzamide    hydrochloride;-   2,6-Difluoro-N-{5-[2-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-pyrazin-2-yl}-benzamide;-   3-[5-(2,6-Difluoro-benzoylamino)-pyrazin-2-yl]-4-methyl-benzoic acid    methyl ester;-   4-Methyl-3-{5-[(3-methyl-pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-benzoic    acid methyl ester;-   3-[5-(2,6-Difluoro-benzoylamino)-pyrazin-2-yl]-4-methyl-benzoic acid    propyl ester;-   3-[5-(2,6-Difluoro-benzoylamino)-pyrazin-2-yl]-4-methyl-benzoic acid    2-methoxy-ethyl ester;-   4-Chloro-3-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-benzoic acid    methyl ester;-   4-Chloro-3-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-benzoic acid    ethyl ester;-   4-Chloro-3-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-benzoic acid    2-methoxy-ethyl ester;-   2,6-Difluoro-N-[5-(5-furan-2-yl-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-benzamide;-   2,6-Difluoro-N-[5-(5-furan-3-yl-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-benzamide;-   N-[5-(5-Chloro-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-2,6-difluoro-benzamide;-   N-[5-(5-Bromo-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-2,6-difluoro-benzamide;-   N-[5-(5-Ethyl-2-trifluoromethyl-phenyl)-pyrazin-2-yl]-2,6-difluoro-benzamide;-   3-[5-(2,6-Difluoro-benzoylamino)-pyrazin-2-yl]-4-methyl-benzamide;-   4-[5-(2,6-Difluoro-benzoylamino)-pyrazin-2-yl]-3-methyl-benzoic acid    methyl ester;-   4-[5-(2,6-Difluoro-benzoylamino)-pyrazin-2-yl]-3-methyl-benzoic acid    ethyl ester;-   4-[5-(2,6-Difluoro-benzoylamino)-pyrazin-2-yl]-3-methyl-benzoic acid    2-methoxy-ethyl ester;-   3-Chloro-4-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-benzoic acid    methyl ester;-   3-Chloro-4-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-benzoic acid    ethyl ester;-   3-Chloro-4-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-benzoic acid    2-methoxy-ethyl ester;-   3-Fluoro-N-[5-(5-furan-2-yl-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-isonicotinamide;-   3-Fluoro-N-[5-(5-furan-3-yl-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-isonicotinamide;-   N-[5-(5-Chloro-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-3-fluoro-isonicotinamide;-   N-[5-(5-Bromo-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-3-fluoro-isonicotinamide;-   3-Fluoro-N-[5-(2-methyl-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   N-[5-(5-Carbamoyl-2-methyl-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide;-   N-[5-(5-Cyano-2-methyl-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide;-   3-{5-[(3,5-Difluoro-pyridine-4-carbonyl)amino]-pyrazin-2-yl}-4-methyl-benzoic    acid methyl ester;-   3-{5-[(3,5-Difluoro-pyridine-4-carbonyl)amino]-pyrazin-2-yl}-4-methyl-benzoic    acid ethyl ester;-   3-{5-[(3,5-Difluoro-pyridine-4-carbonyl)amino]-pyrazin-2-yl}-4-methyl-benzoic    acid 2-methoxy-ethyl ester;-   4-Chloro-3-{5-[(3,5-difluoro-pyridine-4-carbonyl)amino]-pyrazin-2-yl}-benzoic    acid methyl ester;-   4-Chloro-3-{5-[(3,5-difluoro-pyridine-4-carbonyl)amino]-pyrazin-2-yl}-benzoic    acid ethyl ester;-   4-Chloro-3-{5-[(3,5-difluoro-pyridine-4-carbonyl)amino]-pyrazin-2-yl}-benzoic    acid 2-methoxy-ethyl ester;-   3,5-Difluoro-N-[5-(5-furan-2-yl-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-isonicotinamide;-   3,5-Difluoro-N-[5-(5-furan-3-yl-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-isonicotinamide;-   N-[5-(5-Chloro-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide;-   N-[5-(5-Bromo-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide;-   N-[5-(5-Ethyl-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide;-   N-[5-(5-Carbamoyl-2-methyl-phenyl)-pyrazin-2-yl]-3-difluoro-isonicotinamide;-   3,5-Difluoro-N-[5-(5-isocyano-2-methyl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   4-Methyl-3-{5-[(3-methyl-pyridine-4-carbonyl)-amino]pyrazin-2-yl}-benzoic    acid ethyl ester;-   4-Methyl-3-{5-[(3-methyl-pyridine-4-carbonyl)-amino]pyrazin-2-yl}-benzoic    acid 2-methoxy-ethyl ester;-   4-Chloro-3-{5-[(3-methyl-pyridine-4-carbonyl)-amino]pyrazin-2-yl}-benzoic    acid methyl ester;-   4-Chloro-3-{5-[(3-methyl-pyridine-4-carbonyl)-amino]pyrazin-2-yl}-benzoic    acid ethyl ester;-   4-Chloro-3-{5-[(3-methyl-pyridine-4-carbonyl)-amino]pyrazin-2-yl}-benzoic    acid 2-methoxy-ethyl ester;-   N-[5-(2-Chloro-5-furan-2-yl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   N-[5-(2-Chloro-5-furan-3-yl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   N-[5-(5-Chloro-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   N-[5-(5-Bromo-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   N-[5-(2-Ethyl-2-trifluoromethyl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   N-[5-(5-Carbamoyl-2-methyl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   N-[5-(5-Cyano-2-methyl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   2,6-Difluoro-N-[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-benzamide;-   2,6-Difluoro-N-{5-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-pyrazin-2-yl}-benzamide;-   2,6-Difluoro-N-{5-[2-methyl-5-(1H-tetrazol-5-yl)-phenyl]-pyrazin-2-yl}-benzamide;-   3-Fluoro-N-[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   3-Methyl-N-[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   3-Difluoro-N-[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-amide;-   3-Fluoro-N-[5-(2-methyl-5-thiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   3-Methyl-N-[5-(2-methyl-5-thiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   3-Difluoro-N-[5-(2-methyl-5-thiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(2-methyl-5-thiazol-2-yl-phenyl)-pyrazin-2-yl]-amide;-   N-[5-(2-Chloro-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide;-   N-[5-(2-Chloro-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   N-[5-(2-Chloro-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(2-chloro-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-amide;-   3-Fluoro-N-[5-(2-methyl-5-[1,3,4]oxadiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   3-Methyl-N-[5-(2-methyl-5-[1,3,4]oxadiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   3-Difluoro-N-[5-(2-methyl-5-[1,3,4]oxadiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(2-methyl-5-[1,3,4]oxadiazol-2-yl-phenyl)-pyrazin-2-yl]-amide;-   3-Fluoro-N-[5-(2-methyl-5-[1,3,4]thiadiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   3-Methyl-N-[5-(2-methyl-5-[1,3,4]thiadiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   3,5-Difluoro-N-[5-(2-methyl-5-[1,3,4]thiadiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(2-methyl-5-[1,3,4]thiadiazol-2-yl-phenyl)-pyrazin-2-yl]-amide;-   N-[5-(2-Chloro-5-[1,3,4]oxazol-2-yl-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide;-   N-[5-(2-Chloro-5-[1,3,4]oxazol-2-yl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   N-[5-(2-Chloro-5-[1,3,4]-oxazol-2-yl-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(2-chloro-5-[1,3,4]oxadiazol-2-yl-phenyl)-pyrazin-2-yl]-amide;-   3-Fluoro-N-[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   3-Methyl-N-[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   3,5-Difluoro-N-[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-amide;-   3-Fluoro-N-[5-(2-methyl-5-thiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   3-Methyl-N-[5-(2-methyl-5-thiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   3,5-Difluoro-N-[5-(2-methyl-5-thiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(2-methyl-5-thiazol-5-yl-phenyl)-pyrazin-2-yl]-amide;-   N-[5-(2-Chloro-5-oxazol-5-yl-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide;-   N-[5-(2-Chloro-5-oxazol-5-yl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   N-[5-(2-Chloro-5-oxazol-5-yl-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(2-chloro-5-oxazol-5-yl-phenyl)-pyrazin-2-yl]-amide;-   3-Fluoro-N-[5-(5-isoxazol-5-yl-2-methyl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   N-[5-(5-Isoxazol-5-yl-2-methyl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   3,5-Difluoro-N-[5-(5-isoxazol-5-yl-2-methyl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(5-isoxazol-5-yl-2-methyl-phenyl)-pyrazin-2-yl]-amide;-   3-Fluoro-N-[5-(5-isothiazol-5-yl-2-methyl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   N-[5-(5-Isothiazol-5-yl-2-methyl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   3,5-Difluoro-N-[5-(5-isothiazol-5-yl-2-methyl-phenyl)-pyrazin-2-yl]-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(5-isothiazol-5-yl-2-methyl-phenyl)-pyrazin-2-yl]-amide;-   N-[5-(2-Chloro-5-isoxazol-5-yl-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide;-   N-[5-(2-Chloro-5-isoxazol-5-yl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   N-[5-(2-Chloro-5-isoxazol-5-yl-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(2-chloro-5-isoxazol-5-yl-phenyl)-pyrazin-2-yl]-amide;-   3-{5-[(3-Fluoro-pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-4-methyl-benzoic    acid methyl ester;-   N-[5-(2,5-Dimethoxy-phenyl)-pyrazin-2-yl]-2,6-difluoro-benzamide;-   N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-2-methyl-nicotinamide;-   Cyclohexanecarboxylic acid    [5-(2-chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-amide;-   N-[5-(2,5-Dimethoxy-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(2-chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-amide;-   N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide;-   N-[5-(2,5-Dimethoxy-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide;-   N-[5-(2,5-Dimethoxy-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    [5-(2,5-dimethoxy-phenyl)-pyrazin-2-yl]-amide;-   Cyclohexanecarboxylic acid    [5-(2,5-dimethoxy-phenyl)-pyrazin-2-yl]-amide;-   Cyclohexanecarboxylic acid    [5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-amide; and    -   pharmaceutically acceptable salts, solvates, clathrates, or        prodrugs thereof.

In another embodiment, the invention relates toN-[6-(2-chloro-5-trifluoromethyl-phenyl)-pyridazin-3-yl]-2,6-difluoro-benzamide,and a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, the invention relates toN-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrimidin-2-yl]-2,6-difluoro-benzamide,N-[2-(2-Chloro-5-trifluoromethyl-phenyl)-pyrimidin-5-yl]-2,6-difluoro-benzamide,and a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

All of the features, specific embodiments and particular substituentsdisclosed herein may be combined in any combination. Each feature,embodiment or substituent disclosed in this specification may bereplaced by an alternative feature, embodiment or substituent servingthe same, equivalent, or similar purpose. In the case of chemicalcompounds, specific values for variables (e.g., values shown in theexemplary compounds disclosed herein) in any chemical formula disclosedherein can be combined in any combination resulting in a stablestructure. Furthermore, specific values (whether preferred or not) forsubstituents in one type of chemical structure may be combined withvalues for other substituents (whether preferred or not) in the same ordifferent type of chemical structure. Thus, unless expressly statedotherwise, each feature, embodiment or substituent disclosed is only anexample of a generic series of equivalent or similar features,embodiments or substituents.

In another embodiment, the invention relates to pharmaceuticalcompositions that comprise a compound of any one of formulas (I) through(XIV), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, as an active ingredient, and apharmaceutically acceptable carrier or vehicle. The compositions areuseful for immunosuppression or to treat or prevent inflammatoryconditions, allergic conditions and immune disorders.

In another embodiment, the invention relates to methods forimmunosuppression or for treating or preventing inflammatory conditions,immune disorders, or allergic disorders in a patient in need thereofcomprising administering an effective amount of a compound representedby any one of formulas (I) through (XIV), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, the invention relates to methods forimmunosuppression or for treating or preventing inflammatory conditions,immune disorders, or allergic disorders in a patient in need thereofcomprising administering an effective amount of a pharmaceuticalcomposition that comprises a compound represented by any one of formulas(I) through (XIV), or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof.

In another embodiment, compounds of any one of formulas (I) through(XIV), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, are particularly useful inhibiting immunecell (e.g., T-cells and/or B-cells) activation (e.g., activation inresponse to an antigen) and/or T cell and/or B cell proliferation.Indicators of immune cell activation include secretion of IL-2 by Tcells, proliferation of T cells and/or B cells, and the like. In oneembodiment, immune cell activation and/or T cell and/or B cellproliferation is inhibited in a mammal (e.g., a human), by administeringto the mammal (e.g., human) a compound of any one of formulas (I)through (XIV) or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof.

In another embodiment, compounds of of any one of formula (I) through(XIV), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, can inhibit the production of certaincytokines that regulate immune cell activation. For example, compoundsof any one of formulas (I) through (XIV), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, can inhibit the production of IL-2, IL-4, IL-5, IL-13, GM-CSF,IFN-γ, TNF-α and combinations thereof. In one embodiment, cytokineproduction is inhibited in a mammal (e.g., a human), by administering tothe mammal (e.g., human) a compound of any one of formulas (I) through(XIV) or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof.

In another embodiment, compounds of any one of formulas (I) through(XIV), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, can modulate the activity of one or moreion channel, such as CRAC ion channels, involved in activation of immunecells. In one embodiment, a compound of any one of formulas (I) through(XIV) or Table 1 can inhibit the influx of calcium ions into an immunecell (e.g., T cells, B cells, and/or mast cells) by inhibiting theaction of CRAC ion channels. In general, a decrease in I_(CRAC) currentupon contacting a cell with a compound is one indicator that thecompound inhibitions CRAC ion channels. I_(CRAC) current can bemeasured, for example, using a patch clamp technique, which is describedin more detail in the examples below. In one embodiment, a compound ofany one of formulas (I) through (XIV) or Table 1 modulates an ionchannel in a mammal (e.g., a human). In one embodiment, the activity ofone or more ion channels is inhibited in a mammal (e.g., a human), byadministering to the mammal (e.g., human) a compound of any one offormulas (I) through (XIV) or Table 1, or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof.

In another embodiment, compounds of of any one of formula (I) through(XIV), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, can inhibit degranulation of mast cell.Inhibition of mast cell degranulation can determined as described in theexperimental section herein or by any method known to those skilled inthe art. In one embodiment, mast cell degranulation is inhibited in amammal (e.g., a human), by administering to the mammal (e.g., human) acompound of any one of formulas (I) through (XIV) or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

Exemplary Compounds of the Invention

Exemplary compounds of the invention are depicted in Table 1 below.

TABLE 1 Com- pound No. Structure Chemical Name 1

N-[5-(2-Chloro-5-trifluoro- methyl-phenyl)-pyrazin-2-yl]-2,6-difluoro-benzamide 2

N-[5-(2-Chloro-5-trifluoro- methyl-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide 3

N-[5-(2-Chloro-5-trifluoro- methyl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide 4

N-(5-(2-Chloro-5-trifluoro- methyl-phenyl)-pyrazin-2-yl]-2,6-difluoro-benzamid hydrochloride 5

2,6-Difluoro-N-{5-[2-methyl- 5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-pyrazin-2-yl}- benzamide 6

3-[5-(2,6-Difluoro-benzoyl- amino)-pyrazin-2-yl]-4- methyl-benzoic acidmethyl ester 7

4-Methyl-3-{5-[(3-methyl- pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-benzoic acid methyl ester 8

3-[5-(2,6-Difluoro-benzoyl- amino)-pyrazin-2-yl]-4- methyl-benzoic acidpropyl ester 9

3-[5-(2,6-Difluoro-benzoyl- amino)-pyrazin-2-yl]-4- methyl-benzoic acid2-methoxy-ethyl ester 10

4-Chloro-3-[5-(2,6-difluoro- benzoylamino)-pyrazin-2-yl]- benzoic acidmethyl ester 11

4-Chloro-3-[5-(2,6-difluoro- benzoylamino)-pyrazin-2-yl]- benzoic acidethyl ester 12

4-Chloro-3-[5-(2,6-difluoro- benzoylamino)-pyrazin-2-yl]- benzoic acid2-methoxy-ethyl ester 13

2,6-Difluoro-N-[5-(5-furan-2- yl-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-benzamide 14

2,6-Difluoro-N-[5-(5-furan-3- yl-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-benzamide 15

N-[5-(5-Chloro-2-methoxy- pyridin-3-yl)-pyrazin-2-yl]-2,6-difluoro-benzamide 16

N-[5-(5-Bromo-2-methoxy- pyridin-3-yl)-pyrazin-2-yl]-2,6-difluoro-benzamide 17

N-[5-(2-Ethyl-5-trifluoro- methyl-phenyl)-pyrazin-2-yl]-2,6-difluoro-benzamide 18

3-[5-(2,6-Difluoro-benzoyl- amino)-pyrazin-2-yl]-4- methyl-benzamide 19

4-[5-(2,6-Difluoro-benzoyl- amino)-pyrazin-2-yl]-3- methyl-benzoic acidmethyl ester 20

4-[5-(2,6-Difluoro-benzoyl- amino)-pyrazin-2-yl]-3- methyl-benzoic acidethyl ester 21

4-[5-(2,6-Difluoro-benzoyl- amino)-pyrazin-2-yl]-3- methyl-benzoic acid2- methoxy-ethyl ester 22

3-Chloro-4-[5-(2,6-difluoro- benzoylamino)-pyrazin-2-yl]- benzoic acidmethyl ester 23

3-Chloro-4-[5-(2,6-difluoro- benzoylamino)-pyrazin-2-yl]- benzoic acidethyl ester 24

3-Chloro-4-[5-(2,6-difluoro- benzoylamino)-pyrazin-2-yl]- benzoic acid2-methoxy-ethyl ester 25

3-Fluoro-N-[5-(5-furan-2-yl- 2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-isonicotinamide 26

3-Fluoro-N-[5-(5-furan-3-yl- 2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-isonicotinamide 27

N-[5-(5-Chloro-2-methoxy- pyridin-3-yl)-pyrazin-2-yl]-3-fluoro-isonicotinamide 28

N-[5-(5-Bromo-2-methoxy- pyridin-3-yl)-pyrazin-2-yl]-3-fluoro-isonicotinamide 29

3-Fluoro-N-[5-(2-methyl-5- trifluoromethyl-phenyl)-pyrazin-2-yl]-isonicotinamide 30

N-[5-(5-Carbamoyl-2-methyl- phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide 31

N-[5-(5-Cyano-2-methyl- phenyl)-pyrazin-2-yl]-3- fluoro-isonicotinamide32

3-{5-[(3,5-Difluoro-pyridine- 4-carbonyl)-amino]-pyrazin-2-yl}-4-methyl-benzoic acid methyl ester 33

3-{5-[(3,5-Difluoro-pyridine- 4-carbonyl)-amino]-pyrazin-2-yl}-4-methyl-benzoic acid ethyl ester 34

3-{5-[(3,5-Difluoro-pyridine- 4-carbonyl)-amino]-pyrazin-2-yl}-4-methyl-benzoic acid 2-methoxy-ethyl ester 35

4-Chloro-3-{5-[(3,5-difluoro- pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-benzoic acid methyl ester 36

4-Chloro-3-{5-[(3,5-difluoro- pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-benzoic acid ethyl ester 37

4-Chloro-3-{5-[(3,5-difluoro- pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-benzoic acid 2-methoxy-ethyl ester 38

3,5-Difluoro-N-[5-(5-furan-2- yl-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-isonicotinamide 39

3,5-Difluoro-N-[5-(5-furan-3- yl-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-isonicotinamide 40

N-[5-(5-Chloro-2-methoxy- pyridin-3-yl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide 41

N-[5-(5-Bromo-2-methoxy- pyridin-3-yl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide 42

N-[5-(2-Ethyl-5-trifluoro- methyl-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide 43

N-[5-(5-Carbamoyl-2- methyl-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide 44

3,5-Difluoro-N-[5-(5- isocyano-2-methyl-phenyl)-pyrazin-2-yl]-isonicotinamide 45

4-Methyl-3-{5-[(3-methyl- pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-benzoic acid ethyl ester 46

4-Methyl-3-{5-[(3-methyl- pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-benzoic acid 2- methoxy-ethyl ester 47

4-Chloro-3-{5-[(3-methyl- pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-benzoic acid methyl ester 48

4-Chloro-3-{5-[(3-methyl- pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-benzoic acid ethyl ester 49

4-Chloro-3-{5-[(3-methyl- pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-benzoic acid 2- methoxy-ethyl ester 50

N-[5-(2-Chloro-5-furan-2-yl- phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide 51

N-[5-(2-Chloro-5-furan-3-yl- phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide 52

N-[5-(5-Chloro-2-methoxy- pyridin-3-yl)-pyrazin-2-yl]-3-methyl-isonicotinamide 53

N-[5-(5-Bromo-2-methoxy- pyridin-3-yl)-pyrazin-2-yl]-3-methyl-isonicotinamide 54

N-[5-(2-Ethyl-5-trifluoro- methyl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide 55

N-[5-(5-Carbamoyl-2-methyl- phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide 56

N-[5-(5-Cyano-2-methyl- phenyl)-pyrazin-2-yl]-3- methyl-isonicotinamide57

2,6-Difluoro-N-[5-(2-methyl- 5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-benzamide 58

2,6-Difluoro-N-{5-[2-methyl- 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-pyrazin-2-yl}- benzamide 59

2,6-Difluoro-N-{5-[2-methyl- 5-(1H-tetrazol-5-yl)-phenyl]-pyrazin-2-yl}-benzamide 60

N-[6-(2-Chloro-5-trifluoro- methyl-phenyl)-pyridazin-3-yl]-2,6-difluoro-benzamide 61

3-Fluoro-N-[5-(2-methyl-5- oxazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 62

3-Methyl-N-[5-(2-methyl-5- oxazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 63

3,5-Difluoro-N-[5-(2-methyl- 5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 64

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(2-methyl-5-oxazol-2-yl-phenyl)- pyrazin-2-yl]-amide 65

3-Fluoro-N-[5-(2-methyl-5- thiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 66

3-Methyl-N-[5-(2-methyl-5- thiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 67

3,5-Difluoro-N-[5-(2-methyl- 5-thiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 68

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(2-methyl-5-thiazol-2-yl-phenyl)- pyrazin-2-yl]-amide 69

N-[5-(2-Chloro-5-oxazol-2- yl-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide 70

N-[5-(2-Chloro-5-oxazol-2- yl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide 71

N-[5-(2-Chloro-5-oxazol-2- yl-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide 72

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(2-chloro-5-oxazol-2-yl-phenyl)- pyrazin-2-yl]-amide 73

3-Fluoro-N-[5-(2-methyl-5- [1,3,4]oxadiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 74

3-Methyl-N-[5-(2-methyl-5- [1,3,4]oxadiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 75

3,5-Difluoro-N-[5-(2-methyl- 5-[1,3,4]oxadiazol-2-yl-phenyl)-pyrazin-2-yl]- isonicotinamide 76

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(2-methyl-5-[1,3,4]oxadiazol-2-yl- phenyl)-pyrazin-2-yl]-amide 77

3-Fluoro-N-[5-(2-methyl-5- [1,3,4]thiadiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 78

3-Methyl-N-[5-(2-methyl-5- [1,3,4]thiadiazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 79

3,5-Difluoro-N-[5-(2-methyl- 5-[1,3,4]thiadiazol-2-yl-phenyl)-pyrazin-2-yl]- isonicotinamide 80

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(2-methyl-5-[1,3,4]thiadiazol-2-yl- phenyl)-pyrazin-2-yl]-amide 81

N-[5-(2-Chloro-5- [1,3,4]oxadiazol-2-yl-phenyl)- pyrazin-2-yl]-3-fluoro-isonicotinamide 82

N-[5-(2-Chloro-5- [1,3,4]oxadiazol-2-yl-phenyl)- pyrazin-2-yl]-3-methyl-isonicotinamide 83

N-[5-(2-Chloro-5- [1,3,4]oxadiazol-2-yl-phenyl)-pyrazin-2-yl]-3,5-difluoro- isonicotinamide 84

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(2-chloro-5-[1,3,4]oxadiazol-2-yl- phenyl)-pyrazin-2-yl]-amide 85

3-Fluoro-N-[5-(2-methyl-5- oxazol-5-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 86

3-Methyl-N-[5-(2-methyl-5- oxazol-5-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 87

3,5-Difluoro-N-[5-(2-methyl- 5-oxazol-5-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 88

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(2-methyl-5-oxazol-5-yl-phenyl)- pyrazin-2-yl]-amide 89

3-Fluoro-N-[5-(2-methyl-5- thiazol-5-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 90

3-Methyl-N-[5-(2-methyl-5- thiazol-5-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 91

3,5-Difluoro-N-[5-(2-methyl- 5-thiazol-5-yl-phenyl)-pyrazin-2-yl]-isonicotinamide 92

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(2-methyl-5-thiazol-5-yl-phenyl)- pyrazin-2-yl]-amide 93

N-[5-(2-Chloro-5-oxazol-5- yl-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide 94

N-[5-(2-Chloro-5-oxazol-5- yl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide 95

N-[5-(2-Chloro-5-oxazol-5- yl-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide 96

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(2-chloro-5-oxazol-5-yl-phenyl)- pyrazin-2-yl]-amide 97

3-Fluoro-N-[5-(5-isoxazol-5- yl-2-methyl-phenyl)-pyrazin-2-yl]-isonicotinamide 98

N-[5-(5-isoxazol-5-yl-2- methyl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide 99

3,5-Difluoro-N-[5-(5-isoxazol- 5-yl-2-methyl-phenyl)-pyrazin-2-yl]-isonicotinamide 100

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(5-isoxazol-5-yl-2-methyl-phenyl)- pyrazin-2-yl]-amide 101

3-Fluoro-N-[5-(5-isothiazol-5- yl-2-methyl-phenyl)-pyrazin-2-yl]-isonicotinamide 102

N-[5-(5-isothiazol-5-yl-2- methyl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide 103

3,5-Difluoro-N-[5-(5- isothiazol-5-yl-2-methyl- phenyl)-pyrazin-2-yl]-isonicotinamide 104

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(5-isothiazol-5-yl-2-methyl- phenyl)-pyrazin-2-yl]-amide 105

N-[5-(2-Chloro-5-isoxazol-5- yl-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide 106

N-[5-(2-Chloro-5-isoxazol-5- yl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide 107

N-[5-(2-Chloro-5-isoxazol-5- yl-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide 108

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(2-chloro-5-isoxazol-5-yl-phenyl)- pyrazin-2-yl]-amide 109

3-{5-[(3-Fluoro-pyridine-4- carbonyl)-amino]-pyrazin-2-yl}-4-methyl-benzoic acid methyl ester 110

N-[5-(2,5-Dimethoxy-phenyl)- pyrazin-2-yl]-2,6-difluoro- benzamide 111

N-[5-(2-Chloro-5- trifluoromethyl-phenyl)- pyrazin-2-yl]-2-methyl-nicotinamide 112

Cyclohexanecarboxylic acid [5-(2-chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-amide 113

N-[5-(2,5-Dimethoxy-phenyl)- pyrazin-2-yl]-3-fluoro- isonicotinamide 114

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(2-chloro-5-trifluoromethyl-phenyl)- pyrazin-2-yl]-amide 115

N-[5-(2-Chloro-5- trifluoromethyl-phenyl)- pyrazin-2-yl]-3,5-difluoro-isonicotinamide 116

N-[5-(2-Chloro-5- trifluoromethyl-phenyl)- pyrimidin-2-yl]-2,6-difluoro-benzamide 117

N-[5-(2,5-Dimethoxy-phenyl)- pyrazin-2-yl]-3-methyl- isonicotinamide 118

N-[5-(2,5-Dimethoxy-phenyl)- pyrazin-2-yl]-3,5-difluoro- isonicotinamide119

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [5-(2,5-dimethoxy-phenyl)-pyrazin-2- yl]-amide 120

Cyclohexanecarboxylic acid [5-(2,5-dimethoxy-phenyl)-pyrazin-2-yl]-amide 121

Cyclohexanecarboxylic acid [5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-amide 122

N-[2-(2-Chloro-5- trifluoromethyl-phenyl)- pyrimidin-5-yl]-2,6-difluoro-benzamide

Mechanism of Action

Activation of T-lymphocytes in response to an antigen is dependent oncalcium ion oscillations. Calcium ion oscillations in T-lymphocytes aretriggered through stimulation of the T-cell antigen receptor, andinvolve calcium ion influx through the stored-operatedCa²⁺-release-activated Ca²⁺ (CRAC) channel. In addition, antigen induceddegranulation of mast cells has also been shown to be initiated bycalcium ion in flux. Although the molecular structure of the CRAC ionchannel has not been identified, a detailed electrophysiological profileof the channel exist. Thus, inhibition of CRAC ion channels can bemeasured by measuring inhibition of the I_(CRAC) current. Calcium ionoscillations in T-cells have been implicated in the activation ofseveral transcription factors (e.g., NFAT, Oct/Oap and NFκB) which arecritical for T-cell activation (Lewis, Biochemical Society Transactions(2003), 31:925-929, the entire teachings of which are incorporatedherein by reference). Without wishing to be bound by any theory, it isbelieved that because the compounds of the invention inhibit theactivity of CRAC ion channels, they inhibit immune cell activation.

Methods of Treatment and Prevention

In accordance with the invention, an effective amount of a compound ofany one of formulas (I) through (XIV) or Table 1, or a pharmaceuticallyacceptable salt, solvate, clathrate, and prodrug thereof, or apharmaceutical composition comprising a compound of any one of formulas(I) through (XIV) or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, and prodrug thereof, is administered to a patient inneed of immunosuppression or in need of treatment or prevention of aninflammatory condition, an immune disorder, or an allergic disorder.Such patients may be treatment naïve or may experience partial or noresponse to conventional therapies.

Responsiveness to immunosuppression or of a particular inflammatorycondition, immune disorder, or allergic disorder in a subject can bemeasured directly (e.g., measuring blood levels of inflammatorycytokines (such as IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, IFN-γ and thelike) after administration of a compound of this invention), or can beinferred based on an understanding of disease etiology and progression.The compounds of any one of formulas (I) through (XIV), or Table 1, orpharmaceutically acceptable salts, solvates, clathrates, and prodrugsthereof can be assayed in vitro or in vivo, for the desired therapeuticor prophylactic activity, prior to use in humans. For example, knownanimal models of inflammatory conditions, immune disorders, or allergicdisorders can be used to demonstrate the safety and efficacy ofcompounds of this invention.

Preparation of Compounds of the Invention

In general, the pyrazine compounds of the invention that have amidelinkers are prepared by contacting a 2-halo-5-amino-pyrazine (XV) withan acid chloride (XVI) in the presence of a base to form intermediatecompound (XVII) having an amide linkage (see Scheme I).

Intermediate (XVII) is then reacted with a boric acid/derivative (XVIII)in the presence of Pd(PPh₃)₄ and a base to form pyrazine compounds ofthe invention having amide linkers (XIX) (see Scheme III).

Pyrazine compounds having an amide linker in which the amine group isattached to R₃₃ and the carbonyl group is attached to the pyrazine ringcan be prepared by reacting 2-halo-pyrazine-5-carbonyl chloride (XX)with an amine (XXI) in the presence of a base to form intermediatecompound (XXII) (see Scheme III).

Intermediate (XXII) is then reacted with a boric acid derivative (XVIII)in the presence of Pd(PPh₃)₄ and a base (as in Scheme II) to formpyrazine compounds of the invention.

Compounds of the invention in which L is —NHC(S)— or —C(S)NH— can beprepared by treating compounds having an amide linker with Lawesson'sreagent.

Compounds having —CH₂—NH— or —NH—CH₂— linkers can be prepared bycontacting compounds having —NHC(S)— or —C(S)NH— linkers with Raney Ni.Alternatively, compounds of the invention having a —CH₂—NH— or —NH—CH₂—linker can be prepared by reducing a compound having a —C(O)—NH— or—NH—C(O)— linker, respectively, with, for example, sodium borohydride(see U.S. patent application Ser. No. 10/897,681, filed on Jul. 22,2004, the entire teachings of which are incorporated herein byreference).

Compounds of the invention having —C(O)— linkers can be prepared by aFriedel-Craft acylation reaction by reacting a pyrazine derivative(XXIII) with an acid chloride (XXIV) in the presence of AlCl₃ to form anintermediate (XXV) which can then be reacted with an[1,3,2]dioxaborolan-2-yl-aryl or -heteroaryl (XXVI) in the presence of apalladium catalyst and a base to form a compound of the invention havinga carbonyl linker (XXVII) (see Scheme IV).

Compounds of the invention that have —C(S)— can be prepared fromcompounds that have carbonyl linkers by treating them with Lawesson'sreagent or P₂S₅ in pyridine.

Pyridazine compounds of the invention can be prepared in analogousfashion to that described for pyrazine compounds in Schemes I, II, IIIand IV.

Pyrimidine compounds of the invention can be prepared by coupling aboric acid derivative (XVIII) with a 2-amino-5-halo-pyrimidine (XXVIII)in the presence of a Pd(PhCN)₂Cl₂, 1,4-bis(diphenylphosphino)butane(dppb) and a base to an amino-pyrimidine intermediate (XXIX). Theamino-pyrimidine intermediate (XXIX) is then reacted with an acidchloride in pyridine to form a pyrimidine compound of the invention (seeScheme V).

Alternatively, pyrimidine compounds of the invention can be prepared bycoupling a boric acid derivative (XVIII) with a5-nitro-2-halo-pyrimidine (XXXI) in the presence of Pd(PPh₂)₄ and a baseto form a nitro-pyrimidine intermediate (XXXII). The nitro group of thenitro-pyrimidine intermediate (XXXII) can be reduced by treating it withSnCl₂ to form an amino-pyrimidine intermediate (XXXIII). Theamino-pyrimidine intermediate (XXXIII) can then be coupled to acarboxylic acid derivative in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) to form a pyrimidinecompound of the invention (XXXV) (see Scheme VI).

Pharmaceutical, Compositions and Dosage Forms

Pharmaceutical compositions and dosage forms of the invention compriseone or more active ingredients in relative amounts and formulated insuch a way that a given pharmaceutical composition or dosage form can beused for immunosuppression or to treat or prevent inflammatoryconditions, immune disorders, and allergic disorders. Preferredpharmaceutical compositions and dosage forms comprise a compound of anyone of formulas (I) through (XIV), or Table 1, or a pharmaceuticallyacceptable prodrug, salt, solvate, or clathrate thereof, optionally incombination with one or more additional active agents.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage formsuitable for mucosal administration may contain a smaller amount ofactive ingredient(s) than an oral dosage form used to treat the sameindication. This aspect of the invention will be readily apparent tothose skilled in the art. See, e.g., Remington's Pharmaceutical Sciences(1990) 18th ed., Mack Publishing, Easton Pa.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms.

The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients can be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines (e.g., N-desmethylvenlafaxineand N,N-didesmethylvenlafaxine) are particularly susceptible to suchaccelerated decomposition. Consequently, this invention encompassespharmaceutical compositions and dosage forms that contain little, ifany, lactose. As used herein, the term “lactose-free” means that theamount of lactose present, if any, is insufficient to substantiallyincrease the degradation rate of an active ingredient. Lactose-freecompositions of the invention can comprise excipients that are wellknown in the art and are listed, for example, in the U.S. Pharmocopia(USP) SP (XXI)/NF (XVI). In general, lactose-free compositions compriseactive ingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. Preferredlactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T, Carstensen (1995) Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 379-80. In effect, water andheat accelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizer” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms of the invention comprise acompound of any one of formulas (I) through (XIV), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereofin an amount of from about 1 mg to about 1000 mg, preferably in anamount of from about 50 mg to about 500 mg, and most preferably in anamount of from about 75 mg to about 350 mg. The typical total dallydosage of a compound of any one of formulas (I) through (XIV), or Table1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof can range from about 1 mg to about 5000 mg per day, preferablyin an amount from about 50 mg to about 1500 mg per day, more preferablyfrom about 75 mg to about 1000 mg per day. It is within the skill of theart to determine the appropriate dose and dosage form for a givenpatient.

Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences (1990) 18th ed., MackPublishing, Easton Pa.

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Onespecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL-RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103J and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrates are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

Controlled Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,839; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

A particular extended release formulation of this invention comprises atherapeutically or prophylactically effective amount of a compound offormula (I) through (XIV), or Table 1, or a pharmaceutically acceptablesalt, solvate, hydrate, clathrate, or prodrug thereof, in spheroidswhich further comprise microcrystalline cellulose and, optionally,hydroxypropylmethylcellulose coated with a mixture of ethyl celluloseand hydroxypropylmethylcellulose. Such extended release formulations canbe prepared according to U.S. Pat. No. 6,274,171, the entire teachingsof which are incorporated herein by reference.

A specific controlled-release formulation of this invention comprisesfrom about 6% to about 40% a compound of any one of formulas (I) through(XIV), or Table 1 by weight, about 50% to about 94% microcrystallinecellulose, NF, by weight, and optionally from about 0.25% to about 1% byweight of hydroxypropyl-methylcellulose, USP, wherein the spheroids arecoated with a film coating composition comprised of ethyl cellulose andhydroxypropylmethylcellulose.

Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to these skilled in the art. Examplesinclude, but are not limited to: Water for injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

Transdermal, Topical, and Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa. and introduction to Pharmaceutical Dosage Forms(1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels. Further, transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidines such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Combination Therapy

The methods for immunosuppression or for treating or preventinginflammatory conditions, allergic disorders, and immune disorders in apatient in need thereof can further comprise administering to thepatient being administered a compound of this invention, an effectiveamount of one or more other active agents. Such active agents mayinclude those used conventionally for immunosuppression or forinflammatory conditions, allergic disorders, or immune disorders. Theseother active agents may also be those that provide other benefits whenadministered in combination with the compounds of this invention. Forexample, other therapeutic agents may include, without limitation,steroids, non-steroidal anti-inflammatory agents, antihistamines,analgesics, immunosuppressive agents and suitable mixtures thereof. Insuch combination therapy treatment, both the compounds of this inventionand the other drug agent(s) are administered to a subject (e.g., humans,male or female) by conventional methods. The agents may be administeredin a single dosage form or in separate dosage forms. Effective amountsof the other therapeutic agents and dosage forms are well known to thoseskilled in the art. It is well within the skilled artisan's purview todetermine the other therapeutic agent's optimal effective-amount range.

In one embodiment of the invention where another therapeutic agent isadministered to a subject the effective amount of the compound of thisinvention is less than its effective amount when the other therapeuticagent is not administered. In another embodiment, the effective amountof the conventional agent is less than its effective amount when thecompound of this invention is not administered. In this way, undesiredside effects associated with high doses of either agent may beminimized. Other potential advantages (including without limitationimproved dosing regimens and/or reduced drug cost) will be apparent tothose of skill in the art.

In one embodiment relating to autoimmune, allergic and inflammatoryconditions, the other therapeutic agent may be a steroid or anon-steroidal anti-inflammatory agent. Particularly useful non-steroidalanti-inflammatory agents, include, but are not limited to, aspirin,ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen,flubofen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam, isoxicam; salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophennol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone and pharmaceutically acceptablesalts thereof and mixtures thereof. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAntiinflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W., Ruddon eds., 9^(th) ed 1996) andGlen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19th ed. 1995) which are hereby incorporated by reference intheir entireties.

Of particular relevance to allergic disorders, the other therapeuticagent may be an antihistamine. Useful antihistamines include, but arenot limited to, loratadine, cetirizine, fexofenadine, desloratadine,diphenhydramine, chlorpheniramine, chlorcyclizine, pyrilamine,promethazine, terfenadine, doxepin, carbinoxamine, clemastine,tripelennamine, brompheniramine, hydroxyzine, cyclizine, meclizine,cyproheptadine, phenindamine, acrivastine, azelastine, levocabastine,and mixtures thereof. For a more detailed description of antihistamines,see Goodman & Gilman's The Pharmacological Basis of Therapeutics (2001)651-57, 10^(th) ed).

Immunosuppressive agents include glucocorticoids, corticosteroids (suchas Prednisone or Solumedrol), T cell blockers (such as cyclosporin A andFK506), purine analogs (such as azathioprine (Imuran)), pyrimidineanalogs (such as cytosine arabinoside), alkylating agents (such asnitrogen mustard, phenylalanine mustard, buslfan, and cyclophosphamide),folic acid antagonists (such as aminopterin and methotrexate),antibiotics (such as rapamycin, actinomycin D, mitomycin C, puramycin,and chloramphenicol), human IgG, antilymphocyte globulin (ALG), andantibodies (such as anti-CD3 (OKT3), anti-CD4 (OKT4), anti-CD5,anti-CD7, anti-IL-2 receptor, anti-alpha/beta TCR, anti-ICAM-1,anti-CD20 (Rituxan), anti-IL-12 and antibodies to immunotoxins).

The foregoing and other useful combination therapies will be understoodand appreciated by those of skill in the art. Potential advantages ofsuch combination therapies include a different efficacy profile, theability to use less of each of the individual active ingredients tominimize toxic side effects, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Other Embodiments

The compounds of this invention may be used as research tools (forexample, as a positive control for evaluating other potential CRACinhibitors, or IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, and/or INF-γinhibitors). These and other uses and embodiments of the compounds andcompositions of this invention will be apparent to those of ordinaryskill in the art.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of compounds of the invention. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe purpose and interest of this invention. The following examples areset forth to assist in understanding the invention and should not beconstrued as specifically limiting the invention described and claimedherein. Such variations of the invention, including the substitution ofall equivalents now known or later developed, which would be within thepurview of those skilled in the art, and changes in formulation or minorchanges in experimental design, are to be considered to fall within thescope of the invention incorporated herein.

EXAMPLES Experimental Rationale

Without wishing to be bound by theory, it is believed that the compoundsof this invention inhibit CRAC ion channels, thereby inhibitingproduction of IL-2 and other key cytokines involved with inflammatory,allergic and immune responses. The examples that follow demonstratethese properties.

Materials and General Methods

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA), ¹H-NMR and ¹³C-NMRspectra were recorded on a Varian 300 MHz NMR spectrometer. Significantpeaks are tabulated in the order: δ (ppm): chemical shift, multiplicity(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s,broad singlet), coupling constant(s) in Hertz (Hz) and number ofprotons.

Patch clamp experiments were performed in the tight-seal whole-cellconfiguration at 21-25° C. High resolution current recordings wereacquired by a computer-based patch clamp amplifier system (EPC-9, HEKA,Lambrecht, Germany). Patch pipettes had resistances between 2-4 MΩ afterfilling with the standard intracellular solution. Immediately followingestablishment of the whole-cell configuration, voltage ramps of 50-200ms duration spanning the voltage range of −100 to +100 mV were deliveredat a rate of 0.5 Hz over a period of 300-400 seconds. All voltages werecorrected for a liquid junction potential of 10 mV between external andinternal solutions when using glutamate as the intracellular anion.Currents were filtered at 2.9 kHz and digitized at 10 μs intervals.Capacitive currents and series resistance were determined and correctedbefore each voltage ramp using the automatic capacitance compensation ofthe EPC-9. The low resolution temporal development of membrane currentswas assessed by extracting the current amplitude at −80 mV or +80 mVfrom individual ramp current records.

Example 1 Synthesis of Representative Exemplary Compounds of thisInvention

In general, the compounds of the invention can be synthesized usingmethods analogous to those described in U.S. patent application Ser. No.10/897,681 and U.S. Provisional Patent Application Ser. No. 60/611,913,the entire teachings of these patent applications are incorporatedherein by reference.

Compound 1N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-2,6-difluoro-benzamide

Step A: To a stirred solution of 2-bromo-5-amino-pyrazine (24 mmol),triethyl amine (TEA) (5 ml) in dry dichloromethane (DCM) (50 mL) at 0°C. was added 2,6-difluoro-benzoyl chloride (3.0 mL, 24 mmol) dropwise.The mixture was allowed to warm to to room temperature over 2 h beforeit was washed with water (2×100 mL) and dried. Removal of solvents gaveN-(5-bromo-pyrazin-2-yl)-2,6-difluorobenzamide (b) as white solid.

A mixture of 2-chloro-5-trifluoromethyl-benzeneboronic acid (a, 5 mmol),N-(5-bromo-pyrazin-2-yl)-2,6-difluoro-benzamide (b, 5 mmol), palladiumcatalyst (0.30 mmol), potassium carbonate (1 g) in dry 1,4-dioxane (20mL) was heated at 100° C. for 24 h. The mixture was taken up with ethylacetate (EtOAc) (100 mL), washed with water (2×100 mL) and dried overNa₂SO₄. The oil obtained on concentration was purified by flashchromatography followed by recrystallization to give Compound 1 as ayellowish solid (0.19 g).

¹H-NMR (CDCl₃) δ 9.81 (s, 1H), 9.3 (br, 1H), 8.5 (d, 1H, J=2), 7.91 (s,1H), 7.6 (d, 2H, J=2), 7.4 (m, 1H), 7.0 (t, 2H, J=8) ppm; ESMS calcd forC₁₈H₉ClF₅N₃O: 413.0. found: 413.9 (M+H⁺).

Compound 2N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-3-fluoro-isonicotinamide

Compound 2 was prepared in an analogous fashion to Compound 1 exceptthat 3-fluoro-isonicotinoyl chloride was used instead of2,6-difluoro-benzoyl chloride.

¹H-NMR (CDCl₃) δ 9.81 (s, 1H), 9.1 (br, 1H), 8.6-8.8 (m, 3H), 8.1 (t,1H, J=8), 7.98 (s, 1H), 7.66 (s, 2H), 7.26 (s, 1H) ppm; ESMS calcd forC₁₇H₉ClF₄N₄O: 396.0. found: 397.0 (M+H⁺).

Compound 3N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide

Compound 3 was prepared in an analogous fashion to Compound 1 exceptthat 3-methyl-isonicotinoyl chloride was used instead of2,6-difluoro-benzoyl chloride.

¹H-NMR (CDCl₃) δ 9.8 (d, 1H, J=3), 8.7 (d, 1H, J=3); 8.6 (m, 2H), 8.43(s, 1H), 7.96 (s, 1H), 7.6 (d, 2H, J=5), 7.4 (d, 1H, J=5), 7.2 (d, 1H,J=5), 2.55 (s, 3H) ppm; ESMS calcd for C₁₆H₁₂ClF₃N₄O: 392.1. found:393.0 (M+H⁺).

Compound 4N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-2,6-difluoro-benzamidehydrochloride

Compound 4 was prepared by suspending Compound 1 in methanol andbubbling HCl gas through the suspension until all solids went intosolution. The solvent was then removed to give Compound 4, the HCl saltof Compound 1.

¹H-NMR (DMSO-d₆) δ 11.91 (s, 1H), 9.6 (br, 1H), 8.9 (d, 1H, J=2), 8.05(s, 1H), 7.91 (s, 2H), 7.6 (m, 1H), 7.3 (t, 2H, J=8), 3.8 (br, 1H), ppm;ESMS calcd for C₁₆H₁₀Cl₂F₅N₃O: 449.0. found: 413.9 (M−Cl⁻).

Compound 60N-[6-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-3-yl]-2,6-difluoro-benzamide

Compound 60 was prepared in an analogous fashion to Compound 1 exceptthat 3-bromo-6-amino-pyridazine was used instead of2-bromo-5-amino-pyrazine.

¹H-NMR (CDCl₃) δ 9.5 (br, 1H), 8.7 (d, 1H, J=9), 8.0 (t, 1H, J=9); 8.0(br, 1H), 7.7 (d, 2H, J=2), 7.4 (m, 1H), 7.0 (t, 2H, J=8) ppm; ESMScalcd for C₁₈H₉ClF₅N₃O: 413.0. found: 414.0 (M+H⁺).

The compounds listed below were prepared by a method analogous to thatdescribed for Compound 1, 2, 3, 4, and 60

Compound 6 3-[5-(2,6-Difluoro-benzylamino-pyrazin-2-yl]-4-methyl-benzoicacid methyl ester

¹H-NMR (CDCl₃) δ 9.77 (s, 1H), 8.4 (m, 2H), 8.11 (s, 1H), 8.0 (d, 1H,J=8), 7.5 (m, 1H), 7.4 (d, 1H, J=8), 7.1 (t, 2H, J=8), 3.93 (s, 3H),2.48 (s, 3H) ppm; ESMS calcd for C₂₀H₁₅F₂N₃O₃: 383.1. found: 384.0(M+H⁺).

Compound 323-{5-[((3,5-Difluoro-pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-4-methyl-benzoicacid methyl ester

¹H-NMR (CDCl₃) δ 9.8 (br, 1H), 8.6 (m, 2H), 8.48 (s, 2H), 8.10 (s, 1H),8.0 (d, 1H, J=8), 7.4 (d, 1H, J=8), 3.92 (s, 3H), 2.47 (s, 3H) ppm; ESMScalcd for C₁₉H₁₄F₂N₄O₃; 384.1; found: 385.0 (M+H⁺).

Compound 572,6-Difluoro-N-[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-benzamide

¹H-NMR (CDCl₃) δ 9.79 (s, 1H), 8.87 (s, 1H), 8.4 (d, 1H, J=2), 8.1 (d,1H, J=2), 8.0 (d, 1H, J=8), 7.72 (s, 1H), 7.5 (m, 2H), 7.3 (d, 1H, J=8),7.1 (t, 2H, J=8), 2.47 (s, 3H) ppm; ESMS calcd for C₂₁H₁₄F₂N₄O₂: 392.1;found: 393.1 (M+H⁺).

Compound 613-Fluoro-N-[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]isonicotinamide

¹H-NMR (CDCl₃) δ 9.78 (s, 1H), 8.86 (s, 1H), 8.6 (m, 2H), 8.42 (s, 1H),8.14 (s, 1H), 8.0 (d, 1H, J=3), 7.70 (s, 1H), 7.4 (m, 2H), 7.20 (s, 1H),2.52 (s, 3H), 2.43 (s, 3H) ppm; ESMS calcd for C₂₀H₁₄FN₅O₂: 375.1;found: 376.1 (M+H⁺).

Compound 623-Methyl-N-[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide

¹H-NMR (CDCl₃) δ 9.78 (s, 1H), 8.86 (s, 1H), 8.6 (m, 2H), 8.42 (s, 1H),8.14 (s, 1H), 8.0 (d, 1H, J=8), 7.70 (s, 1H), 7.4 (m, 2H), 7.20 (s, 1H),2.52 (s, 3H), 2.43 (s, 3H) ppm; ESMS calcd for C₂₁H₁₇N₅O₂: 371.1; found:372.1 (M+H⁺).

Compound 633,5-Difluoro-N-[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-isonicotinamide

¹H-NMR (CDCl₃) δ 9.73 (s, 1H), 9.11 (br, 1H), 8.5 (m, 3H), 8.17 (s, 1H),8.0 (d, 1H, J=8), 7.70 (s, 1H), 7.4 (d, 1H, J=8), 7.18 (s, 1H), 2.48 (s,3H) ppm; ESMS calcd for C₂₀H₁₃F₂N₅O₂: 393.1; found: 394.1 (M+H⁺).

Compound 64 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-amide

¹H-NMR (CDCl₃) δ 9.69 (s, 1H), 8.52 (s, 1H), 8.4 (br, 1H), 8.14 (s, 1H),8.0 (d, 1H, J=8), 7.73 (s, 1H), 7.4 (d, 1H, J=8), 7.2 (m, 1H), 3.06 (s,3H), 2.48 (s, 3H) ppm; ESMS calcd for C₁₈H₁₄N₆O₂S: 378.1. found: 379.1(M+H⁺).

Compound 1093-{5-[(3-Fluoro-pyridine-4-carbonyl)-amino]-pyrazin-2-yl}-4-methyl-benzoicacid methyl ester

¹H-NMR (CDCl₃) δ 9.77 (s, 1H), 9.0 (br, 1H), 8.7 (m, 2H), 8.50 (s, 1H),8.1 (m, 3H), 7.4 (d, 1H, J=8), 3.93 (s, 3H), 2.49 (s, 3H) ppm; ESMScalcd for C₁₉H₁₅FN₄O₃: 386.1. found: 367.1 (M+H⁺).

Composition 110N-[5-(2,5-Dimethoxy-phenyl)-pyrazin-2-yl]2,6-difluoro-benzamide

¹H-NMR (CDCl₃) δ 9.78 (s, 1H), 9.2 (br, 1H), 8.67 (s, 1H), 7.4 (m, 2H),7.0 (m, 4H), 3.83 (s, 6H) ppm; ESMS calcd for C₁₉H₁₅F₂N₃O₃: 371.1;found: 372.1 (M+H⁺).

Compound 111N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]2-methyl-nicotinamide

¹H-NMR (CDCl₃) δ 9.81 (s, 1H), 8.7 (m, 2H), 8.3 (br, 1H), 7.96 (s, 1H),7.9 (d, 1H, J=8), 7.65 (s, 2H), 7.3 (m, 1H), 2.81 (s, 3H) ppm; ESMScalcd for C₁₈H₁₂ClF₃N₄O: 392.1. found: 393.0 (M+H⁺).

Compound 112 Cyclohexanecarboxylic acid[5-(2-chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-amide

¹H-NMR (CDCl₃) δ 9.68 (s, 1H), 8.67 (s, 1H), 7.9 (m, 2H), 7.63 (s, 2H),2.4 (m, 1H), 2.0 (m, 2H), 1.2-1.9 (m, 8H) ppm; ESMS calcd forC₁₈H₁₇ClF₃N₃O₃: 383.1; found: 384.1 (M+H⁺).

Compound 113N-[5-(2,5-Dimethoxy-phenyl)-pyrazin-2-yl]3-fluoro-isonicotinamide

¹H-NMR (CDCl₃) δ 9.73 (s, 1H), 9.0 (br, 1H), 8.99 (s, 1H), 8.7 (m, 2H),8.0 (m, 1H), 7.51 (s, 1H), 7.0 (m, 2H), 3.86 (s, 6H) ppm; ESMS calcd forC₁₈H₁₅FN₄O₃: 354.1. found: 355.1 (M+H⁺).

Compound 114 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid[5-(2-chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-amide

¹H-NMR (CDCl₃) δ 9.73 (s, 1H), 8.75 (s, 1H), 8.6 (br, 1H), 7.96 (s, 1H),7.66 (s, 2H), 3.05 (s, 3H) ppm; ESMS calcd for C₁₅H₉ClF₃N₅OS: 399.0.found: 400.0 (M+H⁺).

Compound 115N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide

¹H-NMR (CDCl₃) δ 9.78 (s, 1H), 8.76 (s, 1H), 8.58 (s, 2H), 8.5 (br, 1H),7.96 (s, 1H), 7.66 (s, 2H) ppm; ESMS calcd for C₁₇H₈ClF₅N₄O: 414.0.found: 415.0 (M+H⁺).

Compound 117N-[5-(2,5-Dimethoxy-phenyl)-pyrazin-2-yl]-3-methyl-isonicotinamide

¹H-NMR (CDCl₃) δ 9.71 (s, 1H), 8.92 (s, 1H), 8.6 (m, 2H), 8.2 (br, 1H),7.5 (m, 2H), 7.0 (m, 2H), 3.87 (s, 6H), 2.55 (s, 3H) ppm; ESMS calcd forC₁₉H₁₈N₄O₃: 350.1; found: 351.1 (M+H⁺).

Compound 118N-[5-(2,5-Dimethoxy-phenyl)-pyrazin-2-yl]-3,5-difluoro-isonicotinamide

¹H-NMR (CDCl₃) δ 9.70 (s, 1H), 9.0 (br, 1H), 8.89 (s, 1H), 8.51 (s, 2H),7.49 (s, 1H), 6.96 (s, 2H), 3.85 (s, 6H) ppm; ESMS calcd forC₁₈H₁₄F₂N₄O₃: 372.1; found: 373.1 (M+H⁺).

Compound 119 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid[5-(2,5-dimethoxy-phenyl)-pyrazin-2-yl]-amide

¹H-NMR (CDCl₃) δ 9.65 (s, 1H), 8.96 (s, 1H), 8.8 (br, 1H), 7.5 (d, 1H,J=2), 7.4 (d, 1H, J=2), 7.26 (s, 1H), 6.8 (m, 2H), 6.37 (s, 1H), 3.85(s, 6H), 3.03 (s, 3H) ppm; ESMS calcd for C₁₆H₁₅N₅O₃S: 357.1. found:358.1 (M+H⁺).

Compound 120 Cyclohexanecarboxylic acid[5-(2,5-dimethoxy-phenyl)-pyrazin-2-yl]-amide

¹H-NMR (CDCl₃) δ 8.92 (s, 1H), 8.86 (s, 1H), 8.0 (br, 1H), 7.46 (s, 1H),6.95 (s, 2H), 3.84 (s, 6H), 2.4 (m, 1H), 1.4-2.1 (m, 10H) ppm; ESMScalcd for C₁₉H₂₃N₃O₃: 341.2. found: 342.1 (M+H⁺).

Compound 121 Cyclohexanecarboxylic acid[5-(2-methyl-5-oxazol-2-yl-phenyl)-pyrazin-2-yl]-amide

¹H-NMR (CDCl₃) δ 9.64 (d, 1H, J=2), 8.42 (d, 1H, J=2), 8.1 (d, 1H, J=2),8.0 (dd, 1H, J₁=8, J₂=2), 7.9 (br, 1H), 7.71 (s, 1H), 7.4 (d, 1H, J=8),7.2 (m, 2H), 2.43 (s, 3H), 2.4 (m, 1H), 1.4-2.1 (m, 10H) ppm; calcd forC₂₁H₂₂N₄O₂: 362.2; found: 363.2 (M+H⁺).

Compound 116N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-pyrimidin-2-yl]-2,6-difluoro-benzamide

A mixture of 2-chloro-5-trifluoromethyl-benzeneboronic acid (c, 1.5mmol), 5-bromo-pyrimidin-2-ylamine (d, 1.5 mmol), Pd(PhCN)₂Cl₂ (0.10mmol), DPPB (0.10 mmol), sodium bicarbonate (2 mmol) in a mixture oftoluene (20 mL), water (5 mL), ethanol (2 mL) was heated at 100° C. 24h. The mixture was taken up with ethyl acetate (EtOAc) (100 mL), washedwith wafer (2×100 mL) and dried (Na₂SO₄). The oil obtained onconcentration was purified by flash chromatography to give e as a whitesolid (0.26 g).

The above aminopyrimidine e (0.26 g, 0.9 mmol) was dissolved indichloromethane (DCM) (5 mL) and pyridine (0.1 mL) and2,6-difluorobenzoyl chloride (0.9 mmol) was added. The reaction wasstirred for 24 h. Removal of solvent and column purification gaveN-[5-(2-chloro-5-trifluoromethyl-phenyl)-pyrimidin-2-yl]-2,6-difluoro-benzamide(Compound 116, 10 mg) as white solid.

¹H-NMR (CDCl₃) δ 8.9 (br, 1H), 8.70 (s, 2H), 7.7 (m, 2H), 7.57 (s, 1H),7.4 (m, 1H), 7.0 (t, 2H, J−8) ppm; ESMS calcd for C₁₈H₉ClF₅N₃O: 413.0.found: 414.0 (M+H⁺).

Compound 122N-[2-((2-Cloro-5-trifluoromethyl-phenyl)-pyrimidin-5-yl]-2,6-difluoro-benzamide

A mixture of 2-chloro-5-trifluoromethyl-benzeneboronic acid (c, 200 mg),2-chloro-5-nitro-pyrimidine (f, 100 mg), Pd(PPh₃)₄ (0.05 mmol), sodiumbicarbonate (2 mmol) in a mixture of toluene (20 mL), water (5 mL),ethanol (2 mL) was heated at 80° C. for 24 h. The mixture was taken upwith EtOAc (100 mL), washed with water (2×100 mL) and dried (Na₂SO₄).The oil obtained on concentration was passed through a layer of silicagel to get compound g as a crude mixture.

The above mixture was treated with SnCl₂ (200 mg) in ethanol (EtOH) (5mL) for 16 h. The mixture was diluted with water (50 mL) and extractedwith DCM (2×50 mL). The DCM layer was dried, evaporated and passedthrough silica gel to afford compound h as a crude mixture.

The above mixture was treated with 2,6-difluorobenzoic acid (100 mg) andEDC (150 mg) in DCM (5 mL) for 16 h. The mixture was washed with waterand purified by column chromatography to giveN-[2-(2-chloro-5-trifluoromethyl-phenyl)-pyrimidin-5-yl]-2,6-difluoro-benzamideas white solid (Compound 122, 10 mg).

¹H-NMR (CDCl₃) δ 9.28 (s, 2H), 8.09 (s, 1H), 8.0 (br, 1H), 7.63 (s, 2H),7.5 (m, 1H), 7.1 (t 2H, J=8) ppm; ESMS calcd for C₁₈H₉ClF₅N₃O: 413.0.found: 414.0 (M+H⁺).

Example 2 Inhibition of IL-2 Production

Jurkat cells were placed in a 96 well plate (0.5 million cells per wellin 1% FBS medium) then a test compound of this invention was added atdifferent concentrations. After 10 minutes, the cells were activatedwith PHA (final concentration 2.5 μg/mL) and incubated for 20 hours at37° C. under CO₂. The final volume was 200 μL. Following incubation, thecells were centrifuged and the supernatants collected and stored at −70°C. prior to assaying for IL-2 production. A commercial ELISA kit (IL-2Eli-pair, Diaclone Research, Besancon, France) was used to detectproduction of IL-2, from which dose response curves were obtained. TheIC₅₀ value was calculated as the concentration at which 50% of maximumIL-2 production after stimulation was inhibited versus a non-stimulationcontrol.

Compound # IC₅₀ 1 2 nM 2 115 nM 4 6 nM 60 >1000 nM 61 50.5 nM 62 32.2 nM63 18.5 nM 64 55.0 nM 109 49.2 nM 110 15.7 nM 111 133.1 nM 112 22.3 nM113 207.2 nM 114 61.6 nM 115 4.1 nM 116 118.2 nM 117 144.7 nM 118 34.0nM 119 302.4 nM 120 352.5 nM 121 38.5 nM 122 653.8 nM

Inhibition of other cytokines, such as IL-4, IL-5, IL-13; GM-CSF, TNF-α,and INF-γ, can be tested in a similar manner using a commerciallyavailable ELISA kit for each cytokine.

Example 3 Patch Clamp Studies of Inhibition of I_(CRAC) Current in RBLCells, Jurkat Cells, and Primary T Cells

In general, a whole cell patch clamp method was used to examine theeffects of a compound of the invention on a channel that mediatesI_(CRAC). In such experiments, a baseline measurement was establishedfor a patched cell. Then a compound to be tested was perfused (orpuffed) to cells in the external solution and the effect of the compoundon I_(CRAC) was measured. A compound that modulates I_(CRAC) (e.g.,inhibits) is a compound that is useful in the invention for modulatingCRAC ion channel activity.

1) RBL Cells Cells

Rat basophilic leukemia cells (RBL-2H3) were grown in DMEM mediasupplemented with 10% fetal bovine serum in an atmosphere of 95% air/5%CO₂. Cells were seeded on glass coverslips 1-3 days before use.

Recording Conditions

Membrane currents of individual cells were recorded using the whole-cellconfiguration of the patch clamp technique with an EPC10 (HEKAElectronik, Lambrecht, Germany). Electrodes (2-5 MΩ in resistance) werefashioned from borosilicate glass capillary tubes (Sutter Instruments,Novato, Ca.). The recordings were done at room temperature.

Intracellular Pipette Solution

The intracellular pipette solution contained Cs-Glutamate 120 mM; CsCl20 mM; CsBAPTA 10 mM; GsHEPES 10 mM; NaCl 8 mM; MgCl₂ 1 mM; IP3 0.02 mM;pH=7.4 adjusted with CsOH. The solution was kept on ice and shieldedfrom light before the experiment was preformed.

Extracellular Solution

The extracellular solution contained NaCl 138 mM; NaHEPES, 10 mM; CsCl10 mM; CaCl₂ 10 mM; Glucose 5.5 mM; KCl 5.4 mM; KH₂PO₄ 0.4 mM;Na₂HPO₄.H₂O 0.3 mM at pH=7.4 adjusted with NaOH.

Compound Treatment

Each compound was diluted from a 10 mM stock in series using DMSO. Thefinal DMSO concentration was always kept at 0.1%.

Experimental Procedure

I_(CRAC) currents were monitored every 2 seconds using a 50 msecprotocol, where the voltage was ramped from −100 mV to +100 mV. Themembrane potential was held at 0 mV between the test ramps. In a typicalexperiment, the peak inward currents would develop within 50-100seconds. Once the I_(CRAC) currents were stabilized, the cells wereperfused with a test compound in the extracellular solution. At the endof an experiment, the remaining I_(CRAC) currents were then challengedwith a control compound (SKF96365, 10 μM) to ensure that the currentcould still be inhibited.

Data Analysis

The I_(CRAC) current level was determined by measuring the inwardcurrent amplitude at −80 mV of the voltage ramp in an off-line analysisusing MATLAB. The I_(CRAC) current inhibition for each concentration wascalculated using peak amplitude in the beginning of the experiment fromthe same cell. The IC₅₀ value and Hill coefficient for each compound wasestimated by fitting all the individual data points to a single Hillequation.

Results

The table below shows the concentration of a compound of the inventionwhich inhibits 50% of the I_(CRAC) current in RBL cells. As can be seenfrom the data in the table, two representative compounds of theinvention inhibit I_(CRAC) current at concentration of 70 nM.

Compound Number IC₅₀  1 70 nM 115 70 nM SKF96365  4 μM

2) Jurkat Cells Cells

Jurkat T cells are grown on glass coverslips, transferred to therecording chamber and kept in a standard modified Ringer's solution ofthe following composition: NaCl 145 mM, KCl 2.8 mM, CsCl 10 mM, CaCl₂ 10mM, MgCl₂ 2 mM, glucose 10 mM, HEPES.NaOH 10 mM, pH 7.2.

Extracellular Solution

The external solution contains 10 mM CaNaR, 11.5 mM glucose and a testcompound at various concentrations.

Intracellular Pipette Solution

The standard intracellular pipette solution contains: Cs-glutamate 145mM, NaCl 8 mM, MgCl₂ 1 mM, ATP 0.5 mM, GTP 0.3 mM, pH 7.2 adjusted withCsOH. The solution is supplemented with a mixture of 10 mM Cs-BAPTA and4.3-5.3 mM CaCl₂ to buffer [Ca²⁺]i to resting levels of 100-150 nM.

Patch-Clamp Recordings

Patch-clamp experiments are performed in the tight-seal whole-cellconfiguration at 21-25° C. High-resolution current recordings areacquired by a computer-based patch-clamp amplifier system (EPC-9, HEKA,Lambrecht, Germany). Sylgard®-coated patch pipettes typically haveresistances between 2-4 MΩ after filling with the standard intracellularsolution. Immediately following establishment of the whole-cellconfiguration, voltage ramps of 50 ms duration spanning the voltagerange of −100 to +100 mV are delivered from a holding potential of 0 mVat a rate of 0.5 Hz over a period of 300 to 400 seconds. All voltagesare corrected for a liquid junction potential of 10 mV between externaland internal solutions. Currents are filtered at 2.3 kHz and digitizedat 100 μs intervals. Capacitive currents and series resistance aredetermined and corrected before each voltage ramp using the automaticcapacitance compensation of the EPC-9.

Data Analysis

The very first ramps before activation of I_(CRAC) (usually 1 to 3) aredigitally filtered at 2 kHz, pooled and used for leak-subtraction of allsubsequent current records. The low-resolution temporal development ofinward currents is extracted from the leak-corrected individual rampcurrent records by measuring the current amplitude at −80 mV or avoltage of choice.

Compounds of the invention are expected to inhibit I_(CRAC) current inJurkat cells.

3) Primary T Cells Preparation of Primary T Cells

Primary T cells are obtained from human whole blood samples by adding100 μL of RosetteSep® human T cell enrichment cocktail to 2 mL of wholeblood. The mixture is incubated for 20 minutes at room temperature, thendiluted with an equal volume of PBS containing 2% FBS. The mixture islayered on top of RosetteSep® DM-L density medium and then centrifugedfor 20 minutes at 1200 g at room temperature. The enriched T cells arerecovered from the plasma/density medium interface, then washed with PBScontaining 2% FBS twice, and used in patch clamp experiments followingthe procedure described for RBL cells.

Compounds of the invention are expected to inhibit I_(CRAC) current inhuman primary T cells.

Example 4 Inhibition of Multiple Cytokines in Primary Human PBMCs

Peripheral blood mononuclear cells (PBMCs) are stimulated withphytohemagglutinin (PHA) in the presence of varying concentrations ofcompounds of the invention or cyclosporine A (CsA), a known inhibitor ofcytokine production. Cytokine production is measured using commerciallyavailable human ELISA assay kits (from Cell Science, Inc.) following themanufacturers instructions.

The compounds of the invention are potent inhibitors of IL-2, and areexpected to be potent inhibitors of IL-4, IL-5, IL-13, GM-CSF, INF-γ andTNF-α in primary human PBM cells. In addition, compounds of theinvention are not expected to inhibit the anti-inflammatory cytokine,IL-10.

Example 5 Compounds of the Invention are Potent Inhibitors ofDegranulation in RBL Cells Procedure

The day before the assay is performed, RBL cells, that had been grown toconfluence in a 96 well plate, are incubated at 37° C. for at least 2hours. The medium is replaced in each well with 100 μL of fresh mediumcontaining 2 μLg/mL of anti-DNP IgE.

On the following day, the cells are washed once with PRS (2.6 mM glucoseand 0.1% BSA) and 160 μL of PRS was added to each well. A test compoundis added to a well in a 20 μL solution at 10× of the desiredconcentration and incubated for 20 to 40 minutes at 37° C. 20 μL of 10×mouse anti-IgE (10 μL/mL) is added. SKF96365 is used as a positivecontrol. Maximum degranulation typically occurs between 15 to 40 minutesafter addition of anti-IgE.

Results

Compounds of the invention are exported to inhibit degranulation of RBLcells.

Example 6 Compounds of the Invention are Potent Inhibitors of Chemotaxisin T Cells T-Cell Isolation

Twenty ml aliquots of heparinized whole blood (2 pig, 1 human) aresubjected to density gradient centrifugation on Ficoll Hypaque. Thebuffy coal layers representing peripheral blood mononuclear cells(PBMCs) containing lymphocytes and monocytes are washed once,resuspended in 12 ml of incomplete RPMI 1640 and then placed ingelatin-coated T75 culture flasks for 1 hr at 37° C. The non-adherentcells, representing peripheral blood lymphocytes (PBLs) depleted ofmonocytes, are resuspended in complete RPMI media and placed in looselypacked activated nylon wool columns that had been equilibrated with warmmedia. After 1 hr at 37° C., the non-adherent T cell populations areeluted by washing of the columns with additional media. The T cellpreparations are centrifuged, resuspended in 5 ml of incomplete RPMI,and counted using a hemocytometer.

Cell Migration Assay

Aliquots of each T cell preparation are labeled with Calcien AM(Teflabs) and suspended at a concentration of 2.4×10⁶/ml inHEPES-buffered Hank's Balanced Salt Solution containing 1.83 mM CaCl₂and 0.8 mM MgCl₂, pH 7.4 (HHBSS). An equal volume of HHBSS containing 0,20 nM, 200 nM or 2000 nM of compound 1 or 20 nM EDTA is then added andthe cells are incubated for 30 min at 37° C. Fifty μl aliquots of thecell suspensions (60,000 cells) are placed on the membrane (pore size 5μm) of a Neuroprobe ChemoTx 96 well chemotaxis unit that had beenaffixed over wells containing 10 ng/ml MIP-1α In HHBSS. The T cells areallowed to migrate for 2 hr at 37° C., after which the apical surface ofthe membrane is wiped clean of cells. The chemotaxis units are thenplaced in a CytoFlour 4000 (PerSeptive BioSystems) and the fluorescenceof each well is measured (excitation and emission wavelengths of 450 and530 nm, respectively). The number of migrating cells in each well isdetermined from a standard curve generated from measuring thefluorescence of serial two-fold dilutions of the labeled cells placed inthe lower wells of the chemotaxis unit prior to affixing the membrane.

Results: Compounds of the invention are expected to be inhibitory to thechemotactic response of porcine T cells and in human T cells.

All publications, patent applications, patents, and other documentscited herein are incorporated by reference in their entirety. In case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting in any way.

We claim:
 1. A compound represented by structural formula (V′):

or a pharmaceutically acceptable salt thereof, wherein: R₁₂ is phenyloptionally substituted with one or more substituents selected from thegroup consisting of alkyl, haloalkyl, heteroaryl, a halo, cyano, —OR₁₇,—C(X₃)OR₁₇, and —C(X₃)NR₁₅R₁₆; R₁₃ is pyridinyl, which is optionallysubstituted with one or more substituents selected from the groupconsisting of a lower alkyl, a halo, cyano, a lower haloalkyl, and alower alkoxy; R₁₄ is H; R₁₅ and R₁₆, for each occurrence are,independently, H, alkyl, or R₁₅ and R₁₆ are taken together with thenitrogen to which they are attached to form heterocyclyl or heteroaryl;R₁₇ is H, alkyl or cycloalkyl; and X₃ is ═O.
 2. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein said R₁₂ isphenyl, optionally substituted with one or more substituents selectedfrom the group consisting of —CH₃, —CF₃, chloro, cyano, monocyclic5-membered heteroaryl comprising 1 or 2 heteroatoms selected from O andN, —OR₁₇, —C(O)OR₁₇, and —C(O)NH₂; wherein said monocyclic 5-memberedheteroaryl is furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl,isoxazolyl, pyrazolyl, or isothiazolyl.
 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein said R₁₂ is phenyl,optionally substituted with one or more substituents selected from thegroup consisting of —CH₃, —CH₂CH₃, —CF₃, chloro, cyano, —OR₁₇, —C(O)OMe,—C(O)OEt, —C(O)OPr, —C(O)NH₂; furyl, thienyl, pyrrolyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, or isothiazolyl.
 4. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein said R₁₃ is pyridinyl, which is optionally substituted with oneor more substituents selected from the group consisting of an alkyl of 1to 4 carbon atoms and a fluoro atom.
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein said R₁₃ is pyridinyl,which is optionally substituted with one or more substituents selectedfrom the group consisting of methyl and fluoro atom.
 6. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein said R₁₇is methyl, ethyl, n-propyl, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.
 7. A compound represented by structural formula (V′):

or a pharmaceutically acceptable salt thereof, wherein: R₁₂ is phenyloptionally substituted with one or more substituents selected from thegroup consisting of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4carbon atoms, monocyclic 5- or 6-membered heteroaryl comprising 1 or 2heteroatoms selected from O and N, cyano, a halo selected from fluoroand chloro, —OR₁₇, —C(X₃)OR₁₇, and —C(X₃)NR₁₅R₁₆; R₁₃ is pyridinyl,which is optionally substituted with one or more substituents selectedfrom the group consisting of an alkyl of 1 to 4 carbon atoms and afluoro atom; R₁₄ is H; R₁₅ and R₁₆ are H; R₁₇ is H, an alkyl of 1 to 4carbon atoms or cycloalkyl; and X₃ is ═O.
 8. The compound of claim 7, ora pharmaceutically acceptable salt thereof, wherein R₁₂ is phenyl,optionally substituted with one or more substituents selected from thegroup consisting of —CH₃, —CF₃, chloro, cyano, monocyclic 5-memberedheteroaryl comprising 1 or 2 heteroatoms selected from O and N, —OR₁₇,—C(O)OR₁₇, and —C(O)NH₂; R₁₃ is pyridinyl, which is optionallysubstituted with one or more substituents selected from the groupconsisting of an alkyl of 1 to 4 carbon atoms and a fluoro atom; R₁₄ isH; and R₁₇ is alkyl of 1 to 4 carbon atoms or cycloalkyl.
 9. Thecompound of claim 7, or a pharmaceutically acceptable salt thereof,wherein said R₁₇ is phenyl, optionally substituted with one or moresubstituents selected from the group consisting of —CH₃, —CF₃, chloro,cyano, monocyclic 5-membered heteroaryl comprising 1 or 2 heteroatomsselected from O and N, —OR₁₇, —C(O)OR₁₇, and —C(O)NH₂; wherein saidmonocyclic 5-membered heteroaryl is furyl, pyrrolyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, or isothiazolyl, R₁₃ ispyridinyl, which is optionally substituted with one or more substituentsselected from the group consisting of an alkyl of 1 to 4 carbon atomsand a fluoro atom; R₁₄ is H; and R₁₇ is an alkyl of 1 to 4 carbon atomsor cycloalkyl.
 10. The compound of claim 7, or a pharmaceuticallyacceptable salt thereof, wherein said R₁₂ is phenyl, optionallysubstituted with one or more substituents selected from the groupconsisting of —CH₃, —CH₂CH₃, —CF₃, chloro, cyano, —OR₁₇, —C(O)OMe,—C(O)OEt, —C(O)OPr, —C(O)NH₂; furyl, pyrrolyl, oxazolyl, imidazolyl,thiazolyl, isoxazolyl, pyrazolyl, or isothiazolyl; R₁₃ is pyridinyl,which is optionally substituted with one or more substituents selectedfrom the group consisting of methyl and fluoro atom; R₁₄ is H; and R₁₇is an alkyl of 1 to 4 carbon atoms or cycloalkyl.
 11. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of claim 1, or a pharmaceutically acceptable salt thereof.